Involvement of the ERK/HIF-1α/EMT Pathway in XCL1-Induced Migration of MDA-MB-231 and SK-BR-3 Breast Cancer Cells.

Chemokine-receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. Our study found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial-mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in ß-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Notably, the effects of XCL1 on cell migration and intracellular signaling were negated by knockdown of XCR1 using siRNA, confirming XCR1-mediated actions. Treating MDA-MB-231 cells with U0126, a specific mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, blocked XCL1-induced HIF-1α accumulation and cell migration. The effect of XCL1 on cell migration was also evaluated in ER-/HER2+ SK-BR-3 cells. XCL1 also promoted cell migration, EMT induction, HIF-1α accumulation, and ERK phosphorylation in SK-BR-3 cells. While XCL1 did not exhibit any significant impact on the matrix metalloproteinase (MMP)-2 and -9 expressions in MDA-MB-231 cells, it increased the expression of these enzymes in SK-BR-3 cells. Collectively, our results demonstrate that activation of the ERK/HIF-1α/EMT pathway is involved in the XCL1-induced migration of both MDA-MB-231 and SK-BR-3 breast cancer cells. Based on our findings, the XCL1-XCR1 interaction and its associated signaling molecules may serve as specific targets for the prevention of breast cancer cell migration and metastasis.

Mangosteen Pericarp and Its Bioactive Xanthones: Potential Therapeutic Value in Alzheimer's Disease, Parkinson's Disease, and Depression with Pharmacokinetic and Safety Profiles.

Alzheimer's disease (AD), Parkinson's disease (PD), and depression are growing burdens for society globally, partly due to a lack of effective treatments. Mangosteen (Garcinia mangostana L.,) pericarp (MP) and its xanthones may provide therapeutic advantages for these disorders. In this review, we discuss potential therapeutic value of MP-derived agents in AD, PD, and depression with their pharmacokinetic and safety profiles. MP-derived agents have shown multifunctional effects including neuroprotective, antioxidant, and anti-neuroinflammatory actions. In addition, they target specific disease pathologies, such as amyloid beta production and deposition as well as cholinergic dysfunction in AD; α-synuclein aggregation in PD; and modulation of monoamine disturbance in depression. Particularly, the xanthone derivatives, including α-mangostin and γ-mangostin, exhibit potent pharmacological actions. However, low oral bioavailability and poor brain penetration may limit their therapeutic applications. These challenges can be overcome in part by administering as a form of MP extract (MPE) or using specific carrier systems. MPE and α-mangostin are generally safe and well-tolerated in animals. Furthermore, mangosteen-based products are safe for humans. Therefore, MPE and its bioactive xanthones are promising candidates for the treatment of AD, PD, and depression. Further studies including clinical trials are essential to decipher their efficacy, and pharmacokinetic and safety profiles in these disorders.

Anti-Inflammatory and Anti-Migratory Activities of Isoquinoline-1-Carboxamide Derivatives in LPS-Treated BV2 Microglial Cells via Inhibition of MAPKs/NF-κB Pathway.

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 N-(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.

Corrigendum to' Anxiolytic effect of Korean Red Ginseng through upregulation of serotonin and GABA transmission and BDNF expression in immobilized mice' [Journal of Ginseng Research Volume 46, Issue 6, November 2022, Pages 819-829].

[This corrects the article DOI: 10.1016/j.jgr.2022.07.007.].

Anxiolytic effect of Korean Red Ginseng through upregulation of serotonin and GABA transmission and BDNF expression in immobilized mice.

Background: Anxiolytic properties of Korean Red Ginseng (KRG) have been previously reported. However, the exact mechanism(s) of action remains to be elucidated. The present study investigated the effect of KRG on immobilization-induced anxiety-like behaviors in mice and explored the involvement of the serotonin and GABA systems and BDNF in the anxiolytic action. Methods: Mice were orally administered with KRG (200 mg/kg/day) for 4 weeks and immobilized once daily for 2 h. p-Chlorophenylalanine (p-CPA) was intraperitoneally injected on day 22-28, and flumazenil or bicuculline was injected on day 25-28. After behavioral evaluations, brains were dissected for biochemical analyses. Results: KRG improved immobilization-induced anxiety-like behaviors in mice, as assessed by the elevated plus maze (EPM) and marble burying tests (MBT). The anxiolytic effect of KRG was comparable to that of fluoxetine, a reference drug clinically used for anxiety disorders. A serotonin synthesis inhibitor, p-CPA, blocked the effect of KRG in the EPM and MBT, indicating the requirement of serotonin synthesis for anxiolytic action. In addition, the anxiolytic effect of KRG was inhibited by bicuculline (a GABAA antagonist) in MBT, implying the involvement of GABA transmission. Western blotting analyses revealed that KRG upregulated the expression of tryptophan hydroxylase and GABAA receptor in the brain, which was blocked by p-CPA. Enhanced BDNF expression by KRG in the hippocampus was also indicated to mediate the anxiolytic action of KRG in immobilized mice. Conclusion: KRG exhibited the anxiolytic effect in immobilized mice by multiple mechanisms of action, involving enhanced serotonin and GABA transmissions and BDNF expression.

Psychological stress and associated factors among municipal solid waste collectors in Hanoi, Vietnam: A cross-sectional study.

INTRODUCTION: In low and middle-income countries, the manually operated municipal waste collection system prominently depended on the performance of waste collectors (WC). Most of the literature has focused on the impact of waste collection tasks on WCs' physical health, while little was known about the psychological effects of work-related stress. This study aimed to examine the prevalence of psychological stress and related factors among waste collectors in Hanoi, Vietnam. METHODS: A cross-sectional survey was conducted among 802 WCs in 2017. The questionnaire included the 7-item Stress component of the 21-item Depression, Anxiety and Stress Scale, and questions on demographics and work conditions. Descriptive and multivariate logistics regression analyses were conducted to examine the factors related to psychological stress among WCs. RESULTS: Results showed that 13.4% of WCs reported stress symptoms; among them, 3.3% of WCs experienced severe stress. Factors related to lower odds of self-reported psychological stress included self-perceived frequent exposure to high and low temperatures in the working environment (OR = 0.51 and 0.52, respectively). Factors associated with the increased likelihood of symptoms included frequent exposure to hot/flammable objects (OR = 2.41), working a night shift in the last three months (OR = 1.82), education lever lower than high school (OR = 1.82), and having an insufficient monthly income (OR = 1.99). CONCLUSION: The high percentage of workers with severe stress implies the need for mental health prevention and treatment for WCs who participated in this study.

Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers.

Chemokines are chemotactic cytokines that mediate immune cell chemotaxis and lymphoid tissue development. Recent advances have indicated that chemokines and their cognate receptors play critical roles in cancer-related inflammation and cancer progression. On the basis of these findings, the chemokine system has become a new potential drug target for cancer immunotherapy. In this review, we summarize the essential roles of the complex network of chemokines and their receptors in cancer progression. Furthermore, we discuss the potential value of the chemokine system as a cancer prognostic marker. The chemokine system regulates the infiltration of immune cells into the tumor microenvironment, which induces both pro- and anti-immunity and promotes or suppresses tumor growth and proliferation, angiogenesis, and metastasis. Increasing evidence indicates the promising prognostic value of the chemokine system in cancer patients. While CCL2, CXCL10, and CX3CL1/CX3CR1 can serve as favorable or unfavorable prognostic factors depending on the cancer types, CCL14 and XCL1 possess good prognostic value. Other chemokines such as CXCL1, CXCL8, and CXCL12 are poor prognostic markers. Despite vast advances in our understanding of the complex nature of the chemokine system in tumor biology, knowledge about the multifaceted roles of the chemokine system in different types of cancers is still limited. Further studies are necessary to decipher distinct roles within the chemokine system in terms of cancer progression and to validate their potential value in cancer prognosis.

Memory-Enhancing Effects of Mangosteen Pericarp Water Extract through Antioxidative Neuroprotection and Anti-Apoptotic Action.

Mangosteen has long been utilized as a traditional medicine in Southeast Asia. Diverse extracts of mangosteen pericarp and its bioactive xanthones exhibit various bioactivities. However, the pharmacological potential of mangosteen pericarp water extract (MPW) has not been reported yet. This study used primary cultured rat cortical cells to investigate the effect of MPW on neurotoxicity. We found that MPW inhibited neurotoxicity and production of reactive oxygen species triggered by Aß(25-35) or excitatory amino acids. MPW inhibited caspase 3 activation and DNA fragmentation in Aß(25-35)- or N-methyl-D-aspartate-treated cells, suggesting an anti-apoptotic action. Additionally, MPW reduced lipid peroxidation and scavenged 1,1-diphenyl-2-picrylhydrazyl radicals, assuring its antioxidant property. Furthermore, MPW suppressed ß-secretase and acetylcholinesterase activities. These findings prompted us to evaluate its effect on memory dysfunction in scopolamine-treated mice using Morris water maze test. Oral administration of MPW at the dosage of 50, 100, or 300 mg/kg for four days significantly decreased the latency time to find the platform and markedly increased the swimming time in the target quadrant. Taken together, our results suggest that MPW exerts memory-enhancing effect through antioxidative neuroprotection and anti-apoptotic action. Accordingly, MPW may have a potential to prevent or treat memory impairment associated with Alzheimer's disease.