Norgalanthamine has been shown to possess hair-growth promoting effects, including increase in hair-fiber length in cultured rat vibrissa follicles and increase in dermal papilla cell (DPC) ...proliferation. However, the intracellular mechanisms that underlie the action of norgalanthamine in DPCs have not been investigated. In this study, we addressed the ability of norgalanthamine to trigger anagen-activating signaling pathways in DPCs. Norgalanthamine significantly increased extracellular signal-regulated kinase (ERK) 1/2 phosphorylation at 0.1 µM, a concentration at which DPC proliferation was also induced. Furthermore, the increases in norgalanthamine-induced ERK 1/2 activation and subsequent DPC proliferation were suppressed by the mitogen-activated protein kinase/ERK kinase (MEK) 1/2 inhibitor, U0126. A 0.1 µM dose of norgalanthamine also increased phosphorylation of AKT, which was followed by an increase in glycogen synthase kinase 3β phosphorylation and nuclear translocation of β-catenin. In addition, LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, blocked the effect of norgalanthamine on DPC proliferation. These results suggest that norgalanthamine can stimulate the anagen phase of the hair cycle in DPCs via activation of the ERK 1/2, PI3K/AKT, and Wnt/β-catenin pathways.
Air pollution is an emerging cause of mortality, affecting nearly 5 million people each year. Exposure to diesel exhaust fine particulate matter (PM2.5) aggravates respiratory and skin conditions. ...However, its impact on the protective immunity of the skin remains poorly understood. This study aimed to investigate the underlying molecular mechanism for adverse effects of PM2.5 on the host protective immunity using in vitro cell and in vivo mouse model. Intracellular translocation of Toll-like receptor 9 (TLR9) and CpG-DNA internalization were assessed in dendritic cells without or with PM2.5 treatment using immunofluorescence staining. Cytokine and nitric oxide production were measured in dendritic cells and macrophages without or with PM2.5 treatment. NF-κB and MAPK signaling was determined using western blotting. Skin disease severity, bacterial loads, and cytokine production were assessed in cutaneous Staphylococcus aureus (S. aureus) infection mouse model. PM2.5 interfered with TLR9 activation by inhibiting both TLR9 trafficking to early endosomes and CpG-DNA internalization via clathrin-mediated endocytosis. In addition, exposure to PM2.5 inhibited various TLR-mediated nitric oxide and cytokine production as well as MAPK and NF-κB signaling. PM2.5 rendered mice more susceptible to staphylococcal skin infections. Our results suggest that exposure to PM impairs TLR signaling and dampens the host defense against staphylococcal skin infections. Our data provide a novel perspective into the impact of PM on protective immunity which is paramount to revealing air pollutant-mediated toxicity on the host immunity.
•Diesel exhaust particulate matter (PM2.5) impairs TLR9 signaling.•PM2.5 interferes with TLR9 activation by inhibiting TLR9 and CpG-DNA trafficking.•PM2.5 inhibits the production of nitric oxide and cytokines by various TLRs.•PM2.5 renders mice more susceptible to staphylococcal skin infections.
The antitumor activity of fucoidan from Fucus vesiculosus was investigated in human colon carcinoma cells. The crude fucoidan, a polysaccharide composed predominantly of sulfated fucose, markedly ...inhibited the growth of HCT-15 cells (human colon carcinoma cells). After HCT-15 cells were treated with fucoidan, several apoptotic events such as DNA fragmentation, chromatin condensation and increase of the population of sub-G1 hypodiploid cells were observed. In the mechanism of fucoidan-induced apoptosis, we examined changes in Bcl-2 and Bax protein expression levels and activation of caspases. Fucoidan decreased Bcl-2 expression, whereas the expression of Bax was increased in a time-dependent manner compared to the control. In addition, the active forms of caspase-9 and caspase-3 were increased, and the cleavage of poly(ADP-ribose) polymerase (PARP), a vital substrate of effector caspase, was observed. Furthermore, the induction of apoptosis was also accompanied by a strong activation of extracellular signal-regulated kinase (ERK) and p38 kinase and an inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt in a time-dependent manner. These findings provide evidence demonstrating that the pro-apoptotic effect of fucoidan is mediated through the activation of ERK, p38 and the blocking of the PI3K/Akt signal pathway in HCT-15 cells. These data support the hypothesis that fucoidan may have potential in colon cancer treatment.
Climate change affects the survival and transmission of arthropod vectors as well as the development rates of vector-borne pathogens. Increased international travel is also an important factor in the ...spread of vector-borne diseases (VBDs) such as dengue, West Nile, yellow fever, chikungunya, and malaria. Dengue is the most important vector-borne viral disease. An estimated 2.5 billion people are at risk of infection in the world and there are approximately 50 million dengue infections and an estimated 500,000 individuals are hospitalized with dengue haemorrhagic fever annually. The Asian tiger mosquito (Aedes albopictus) is one of the vectors of dengue virus, and populations already exist on Jeju Island, South Korea. Currently, colder winter temperatures kill off Asian tiger mosquito populations and there is no evidence of the mosquitos being vectors for the dengue virus in this location. However, dengue virus-bearing mosquito vectors can inflow to Jeju Island from endemic area such as Vietnam by increased international travel, and this mosquito vector's survival during colder winter months will likely occur due to the effects of climate change.
In this section, we show the geographical distribution of medically important mosquito vectors such as Ae. albopictus, a vector of both dengue and chikungunya viruses; Culex pipiens, a vector of West Nile virus; and Anopheles sinensis, a vector of Plasmodium vivax, within Jeju Island, South Korea. We found a significant association between the mean temperature, amount of precipitation, and density of mosquitoes. The phylogenetic analyses show that an Ae. albopictus, collected in southern area of Jeju Island, was identical to specimens found in Ho Chi Minh, Vietnam, and not Nagasaki, Japan.
Our results suggest that mosquito vectors or virus-bearing vectors can transmit from epidemic regions of Southeast Asia to Jeju Island and can survive during colder winter months. Therefore, Jeju Island is no longer safe from vector borne diseases (VBDs) due to the effects of globalization and climate change, and we should immediately monitor regional climate change to identify newly emerging VBDs.
The skin is the largest organ of the human body and the one mostly exposed to outdoor contaminants. To evaluate the biological mechanisms underlying skin damage caused by fine particulate matter (PM
...2.5
), we analyzed the effects of PM
2.5
on cultured human keratinocytes and the skin of experimental animals. PM
2.5
was applied to human HaCaT keratinocytes at 50 µg/mL for 24 h and to mouse skin at 100 µg/mL for 7 days. The results indicate that PM
2.5
induced oxidative stress by generating reactive oxygen species both in vitro and in vivo, which led to DNA damage, lipid peroxidation, and protein carbonylation. As a result, PM
2.5
induced endoplasmic reticulum stress, mitochondrial swelling, and autophagy, and caused apoptosis in HaCaT cells and mouse skin tissue. The PM
2.5
-induced cell damage was attenuated by antioxidant
N
-acetyl cysteine, confirming that PM
2.5
cellular toxicity was due to oxidative stress. These findings contribute to understanding of the pathophysiological mechanisms triggered in the skin by PM
2.5
, among which oxidative stress may play a major role.
Massa Medicata Fermentata (MMF), known as Shenqu, is an important traditional Chinese medicine widely used to treat indigestion, vomiting, and diarrhea. In this study, a new benzochroman, 3(
...)-3,4-dihydro-5,10-di-
-d-glucopyranoside-2,2-dimethyl-2
-naphtho(2,3-
)pyran-3-ol (
), and five known galactosyl acylglycerols (
⁻
) were isolated from a methanol extract from MMF. In addition, their chemical structures were determined by chemical and spectroscopic methods, which were compared with the previously reported data. Furthermore, the effects of isolated compounds on lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells were investigated. Compounds
⁻
exhibited significant inhibitory effects on the LPS-induced production of IL-6 and IL-12 p40, with IC
values ranging from 1.6 to 10.2 μM. Compounds
and
also exhibited strong inhibitory effects on the LPS-stimulated production of TNF-α with IC
values of 12.0 and 11.2 μM, respectively. The results might provide a scientific basis for the development of the active components in MMF, as well as for novel anti-inflammatory agents.
Abstract Appropriate host‐microbiota interactions are essential for maintaining intestinal homeostasis; hence, an imbalance in these interactions leads to inflammation‐associated intestinal diseases. ...Toll‐like receptors (TLRs) recognize microbial ligands and play a key role in host–microbe interactions in health and disease. TLR13 has a well‐established function in enhancing host defenses against pathogenic bacteria. However, its role in maintaining intestinal homeostasis and controlling colitis‐associated colon cancer (CAC) is largely unknown. This study aimed to investigate the involvement of TLR13‐mediated signaling in intestinal homeostasis and colonic tumorigenesis using ex vivo cell and in vivo CAC animal model. Tlr13 ‐deficient mice were prone to dextran sodium sulfate (DSS)‐induced colitis. During the early stages of the CAC regimen (AOM/DSS‐treated), Tlr13 deficiency led to severe ulcerative colitis. Moreover, Tlr13 ‐deficient mice exhibited increased intestinal permeability, as evidenced by elevated levels of fluorescein isothiocyanate (FITC)‐dextran, endotoxins, and bacterial translocation. Enhanced cell survival and proliferation of colonic intestinal cells were observed in Tlr13 ‐deficient mice. A transcriptome analysis revealed that Tlr13 deficiency is associated with substantial changes in gene expression profile of colonic tumor tissue. Tlr13‐ deficient mice were more susceptible to CAC, with increased production of interleukin (IL)‐6, IL‐12, and TNF‐α cytokines and enhanced STAT3, NF‐κB, and MAPK signaling in colon tissues. These findings suggest that TLR13 plays a protective role in maintaining intestinal homeostasis and controlling CAC. Our study provides a novel perspective on intestinal health via TLR13‐mediated signaling, which is crucial for deciphering the role of host‐microbiota interactions in health and disease.
Ambient particulate matter (PM) is associated with adverse health consequences. However, the influence of PM on the innate immune system is poorly understood. The aim of the present study was to ...examine the effect of diesel particulate matter 2.5 μm (PM
2.5
, SRM1650b) on dendritic cells. PM
2.5
significantly reduced cytokine levels of interleukin (IL)-12 p40, IL-6 and TNF-α levels in CpG-DNA (TLR9 ligand)-stimulated dendritic cells. To determine the mechanisms underlying this observed inhibition induced by PM
2.5
, western blot analysis was conducted. PM
2.5
was found to downregulate ERK1/2, JNK1/2, p38 MAPKs, and NF-κB pathways. PM
2.5
exposure decreased TLR9-dependent NF-κB and activator protein (AP-1) reporter luciferase activities. Our findings demonstrate that PM
2.5
reduced the production of cytokines which may be associated with inhibition of MAPK and NF-κB signaling pathway. Further, data suggest the immunosuppressive effect of PM
2.5
on the innate immune cells may lead to serious damage to the host immune system.
Fucoidan, a sulfated polysaccharide, has a variety of biological activities, such as anti-cancer, anti-angiogenic and anti-inflammatory. However, the mechanisms of action of fucoidan as an ...anti-cancer agent have not been fully elucidated. The present study examined the anti-cancer effect of fucoidan obtained from Undaria pinnatifida in PC-3 cells, human prostate cancer cells. Fucoidan induced the apoptosis of PC-3 cells by activating both intrinsic and extrinsic pathways. The induction of apoptosis was accompanied by the activation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK1/2 MAPK) and the inactivation of p38 MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt. In addition, fucoidan also induced the up-regulation of p21Cip1/Waf and down-regulation of E2F-1 cell-cycle-related proteins. Furthermore, in the Wnt/β-catenin pathway, fucoidan activated GSK-3β that resulted in the decrease of β-catenin level, followed by the decrease of c-myc and cyclin D1 expressions, target genes of β-catenin in PC-3 cells. These results suggested that fucoidan treatment could induce intrinsic and extrinsic apoptosis pathways via the activation of ERK1/2 MAPK, the inactivation of p38 MAPK and PI3K/Akt signaling pathway, and the down-regulation of Wnt/β-catenin signaling pathway in PC-3 prostate cancer cells. These data support that fucoidan might have potential for the treatment of prostate cancer.
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