Hesperidin is a citrus flavanone glycoside with potent anti-inflammatory effects that interferes with UVB-stimulated angiogenesis in skin, but its molecular mechanisms of action remain unclear. Here, ...we investigated the effects of hesperidin on UVB-induced angiogenesis in HR-1 hairless mice. We found hesperidin treatment inhibited skin neovascularization skin induced by repetitive UVB light exposure. Exposure to UVB radiation induces the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase-13 (MMP-13), and MMP-9, but we found all of these were inhibited by treatment with hesperidin. Using immunohistochemistry and Western blotting, we also found hesperidin inhibited the increase in hypoxia inducible factor-1 (HIF-1)α expression induced by UVB exposure. After discovering that UVB induces VEGF expression via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathways, we found hesperidin reduces UVB-induced VEGF expression by inhibiting UVB-induced PI3K activity. This, in turn, reduces the UVB-induced Akt/p70S6K phosphorylation in human primary keratinocytes and fibroblast cells. Because it affects the mediators of angiogenesis, our data suggest hesperidin has an anti-angiogenic effect on the pathologic skin neovascularization induced by UVB light. Thus, hesperidin may prove useful in the treatment of skin injuries caused by UVB light exposure.
TREM2 plays a critical role in the alleviation of Alzheimer's disease by promoting Aβ phagocytosis by microglia, but the detailed molecular mechanism underlying TREM2-induced direct phagocytic ...activity of Aβ remains to be revealed. We found that learning and memory functions were improved in aged TREM2 TG mice, with the opposite effects in KO mice. The amount of phagocytosed Aβ was significantly reduced in the primary microglia of KO mice. CD36 expression in primary microglia was greater in TG than in WT mice but was substantially decreased in KO mice. The expression of C/EBPα, an upstream transcriptional activator of CD36, was also elevated in primary microglia of TG mice but decreased in KO mice. The transcription of CD36 was markedly increased by TREM2 overexpression, and this effect was suppressed by a mutation of the C/EBPα binding site on the CD36 promoter. The TREM2-induced expression of CD36 and C/EBPα was inhibited by treatment with PI3K/AKT signaling blockers, and phosphorylation of AKT was elevated in TREM2-overexpressing BV2 cells. The present study provides evidence that TREM2 is required for preventing loss of memory and learning in Alzheimer's disease by regulating C/EBPα-dependent CD36 expression and the consequent Aβ phagocytosis.
Objectives
Sosihotang (SSH) is an herbal medicine traditionally used against the common cold, and hepatic and gastric diseases, in Northeast Asia. In this study, we investigated whether SSH extract ...can protect against UVB‐induced skin damage and photoageing.
Methods
HaCaT cells were treated with SSH extract and exposed UVB irradiation at 20 mJ/cm2. Hairless mice were orally administered SSH extract (100 mg/kg per mouse) as UVB irradiation was increased from 60 to 120 mJ/cm2 over the course of 12 weeks.
Key findings
Treatment with SSH extract inhibited the upregulation of MMP‐1 and MMP‐9 expression in UVB‐irradiated HaCaT cells. In UVB‐irradiated hairless mice, treatment with SSH extract restored the levels of factors instrumental in skin hydration (TEWL, capacitance, HA and TGF‐β) and those regulating collagen content (procollagen, MMP‐1 and MMP‐9). This activity inhibited epidermal thickening and disorganization of collagen fibres. Administration of SSH extract also ameliorated the expression of UVB‐induced pro‐inflammatory cytokines (TNF‐α, IL‐1β and IL‐6) and phosphorylation of MAPK family members (MEK, JNK, ERK and p38) by upregulating the activity of antioxidant enzymes (SOD, CAT, Nrf‐2, HO‐1 and NQO‐1).
Conclusions
These results indicate that SSH extract can be used therapeutically for the treatment of UVB‐induced skin damage and photoageing.
Allergic rhinitis (AR) is a common chronic respiratory disease. Asarum heterotropoides (AH) is predicted to be a treatment for allergic diseases, but its therapeutic effect is unclear. We aimed to ...determine the anti-allergic effects of AH in mice with ovalbumin (OVA)-induced AR. OVA-induced AR mouse model was constructed, and AH was orally administered for a week; next, nasal clinical symptoms were evaluated. The levels of serum histamine, OVA-specific IgE, and IL-13 were measured by ELISA. Inflammatory cells, including leukocytes, neutrophils, eosinophils, and macrophages were counted in the nasal lavage fluid (NALF). Histopathological examinations of the nasal tissues were performed using H&E, Giemsa, and PAS staining. The production of periostin and eotaxin-3 from AH-treated human nasal epithelial cells (HNEpCs) in vitro, was measured using ELISA. Oral administration of AH alleviated allergic symptoms in mice with AR; significantly decreased levels of allergic mediators, such as serum histamine and OVA-specific IgE. The decrease in allergic symptoms positively correlated with the decrease in serum allergic mediators. The NALF of AH-treated AR mice demonstrated lower number of eosinophils. AH demonstrated a capacity to reduce the infiltration of mast cells, eosinophils, and goblet cells, thereby resulting in thinner nasal tissues. Moreover, treatment of HNEpCs with AH demonstrated suppressed production of periostin and eotaxin-3. AH exerts a therapeutic effect in modulating AR through multi-target and multi-function influence on regulating B cells, mast cells, eosinophils, goblet cells, and epithelial cells.
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•Administration of Asarum heterotropoides (AH) cured allergic symptoms in AR mice.•AH-treated AR mice revealed decreased serum histamine and OVA-specific IgE.•AH treatment reduced nasal thickness in AR mice.•AH treatment reduced the number of eosinophils, mast cells and goblet cells in the nasal tissue.•AH inhibited periostin and eotaxin-3 expression in human nasal epithelial cells.
Georgi and
Linne herbal mixture (SRE) is a Chinese herbal medicine. In this study, we aimed to evaluate the therapeutic efficacy of SRE as an active ingredient for 2,4-dinitrochlorobenzene ...(DNCB)-induced atopic dermatitis (AD) and to predict the underlying therapeutic mechanisms and involved pathways using network pharmacological analysis. Treatment with SRE accelerated the development of AD-like lesions, improving thickness and edema of the epidermis. Moreover, administering the SRE to AD-like mice suppressed immunoglobulin E and interleukin-4 cytokine and reduced T lymphocyte differentiation. In silico, network analysis was used to predict the exact genes, proteins, and pathways responsible for the therapeutic effect of the SRE against DNCB-induced AD. These results indicated that the SRE exerted protective effects on the DNCB-induced AD-like model by attenuating histopathological changes and suppressing the levels of inflammatory mediators. Therefore, the SRE can potentially be a new remedy for improving AD and other inflammatory diseases and predicting the intracellular signaling pathways and target genes involved. This therapeutic effect of the SRE on AD can be used to treat DNCB-induced AD and its associated symptoms.
Effects of Dictamnus dasycarpus Turcz. on allergic asthma and their underlying mechanisms remain unclarified. Thus, we investigated the effects of D. dasycarpus Turcz. water extract (DDW) on mucus ...hypersecretion in mice with ovalbumin (OVA)-induced asthma and human bronchial epithelial cells.
BALB/c mice were used to establish an OVA-induced allergic asthma model. Mice were grouped into the OVA sensitization/challenge, 100 and 300 mg/kg DDW treatment, and dexamethasone groups. In mice, cell counts in bronchoalveolar lavage fluid (BALF), serum and BALF analyses, and histopathological lung tissue analyses were performed. Furthermore, we confirmed the basic mechanism in interleukin (IL)−4/IL-13-treated human bronchial epithelial cells through western blotting.
In OVA-induced asthma mice, DDW treatment reduced inflammatory cell number and airway hyperresponsiveness and ameliorated histological changes (immune cell infiltration, mucus secretion, and collagen deposition) in lung tissues and serum total immunoglobulin E levels. DDW treatment lowered BALF IL-4, IL-5, and IL-13 levels; reduced levels of inflammatory mediators, such as thymus- and activation-regulated chemokine, macrophage-derived chemokine, and interferon gamma-induced protein; decreased mucin 5AC (MUC5AC) production; decreased signal transducer and activator of transcription (STAT) 6 and STAT3 expression; and restored forkhead box protein A2 (FOXA2) expression. In IL-4/IL-13-treated human bronchial epithelial cells, DDW treatment inhibited MUC5AC production, suppressed STAT6 and STAT3 expression (related to mucus hypersecretion), and increased FOXA2 expression.
DDW treatment modulates MUC5AC expression and mucus hypersecretion by downregulating STAT6 and STAT3 expression and upregulating FOXA2 expression. These findings provide a novel approach to manage mucus hypersecretion in asthma using DDW.
Allergic rhinitis (AR), caused by immunoglobulin E (IgE)-mediated inflammation, generally occurs in the upper respiratory tract. T helper type 2 (Th2) cell-mediated cytokines, including interleukin ...(IL)-4, IL-5, and IL-13, are important factors in AR pathogenesis. Despite various treatment options, the difficulty in alleviating AR and pharmacological side effects necessitate development of new therapies. The root of Pulsatilla koreana Nakai (P. koreana), a pasque flower, has been used as a herbal medicine. However, its effects on AR remain unclear; therefore, we aimed to explore this subject in the current study. The therapeutic effects of P. koreana water extract (PKN) on the pathophysiological functions of the nasal mucosa was examined in ovalbumin (OVA)-induced AR mice. The effect of PKN on Th2 activation and differentiation was evaluated using concanavalin A-induced splenocytes and differentiated Th2 cells from naïve CD4+ T cells. We also investigated the effect of changes in JAK/STAT6/GATA3 signaling on IL-4-induced Th2 cells. In OVA-induced AR mice, PKN administration alleviated allergic nasal symptoms and decreased the total number of immune cells, lymphocytes, neutrophils, and eosinophils in nasal lavage fluid; serum levels of OVA-specific IgE, histamine, and IL-13 were also significantly reduced. PKN also ameliorated OVA-induced nasal mucosal tissue thickening by inhibiting inflammation and goblet cell hyperplasia. PKN treatment significantly inhibited Th2 activity and differentiation through the IL-4/STAT-6/GATA3 pathway in Th2 cells. PKN is an effective AR treatment with the potential to improve patients' daily lives by regulating the allergic inflammatory response induced by Th2 cells.
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•The effects of Pulsatilla koreana Nakai (PKN) treatments on allergic rhinitis (AR) are unclear.•PKN was assessed using an AR mouse model, isolated primary splenocytes, and differentiated Th2 cells.•Allergic responses were suppressed by the PKN treatment.•The PKN treatment inhibited Th2 activity and differentiation via IL-4/STAT6/GATA3 pathway.•PKN may be a suitable treatment forTh2-mediated allergic diseases in the future.
Objectives
To compare the presence of washout and the diagnostic performance of computed tomography (CT) and magnetic resonance imaging (MRI) for hepatocellular carcinoma (HCC) according to the ...presence of hepatic steatosis.
Methods
This retrospective study included 566 patients with chronic liver disease who had undergone hepatic resection for hepatic tumors (482 HCCs and 84 non-HCCs) between January 2016 and June 2018 and had available multiphasic CT and MR images. Patients were allocated in the fatty liver (
n
= 141) or non-fatty liver (
n
= 425) group according to the presence of hepatic steatosis, defined as lipid droplets in at least 5% of hepatocytes on pathological examination. The presence of HCC washout and the diagnostic performance of CT and MRI for HCC were compared between the groups.
Results
HCC washout was less frequently seen in the fatty liver group than in the non-fatty liver group on CT (61.5% vs. 88.9%,
p
< 0.001), whereas it was similarly present on MRI in both groups (77.0% vs. 74.4%,
p
= 0.565). For diagnosis of HCC, the sensitivity (53.3% vs. 80.0%,
p
< 0.001) and accuracy (53.9% vs. 80.9%,
p
< 0.001) of CT were lower in the fatty liver group than in the non-fatty liver group. However, for MRI, these values were not significantly different between the groups (
p
> 0.05).
Conclusions
Hepatic steatosis significantly decreased the performance of CT for the diagnosis of HCC, whereas it did not significantly alter the performance of MRI.
Key Points
•
Unlike MRI, there is vanishing HCC washout on CT caused by the background hepatic steatosis
.
•
The diagnostic performance of CT for the diagnosis of HCC was significantly altered by hepatic steatosis
.
•
The optimal cutoff HU value of the liver parenchyma for the vanishing washout of HCC was < 50 HU on unenhanced CT images
.
Allergic rhinitis (AR), a chronic respiratory inflammatory disease, is among the most common chronic diseases reported worldwide. Mucus hypersecretion is a critical feature of AR pathogenesis. ...Although the Gleditsia sinensis extract has several beneficial effects on human health, its effects on allergic inflammation have not yet been investigated. In this study, we examined the effects of G. sinensis aqueous extract (GSAE) on nasal inflammation in an ovalbumin (OVA)-induced AR mouse model. GSAE was administered orally for 1 week and then the clinical nasal symptoms were evaluated. The levels of histamine, OVA-specific immunoglobulin (Ig) E, and interleukin (IL)-13 were measured in the serum using an enzyme-linked immunosorbent assay (ELISA). Inflammatory cells were then counted in the nasal lavage fluid (NALF) and histopathology in the nasal epithelium was evaluated. STAT3/STAT6 phosphorylation was examined in primary human nasal epithelial cells (HNEpCs) using western blot analysis. Oral administration of GSAE to OVA-induced AR mice alleviated nasal clinical symptoms and reduced OVA-specific immunoglobulin E, interleukin (IL)-13, and histamine levels. The accumulation of eosinophils in nasal lavage fluid, nasal mucosa, mast cells, goblet cells, and mucin 5AC (MUC5AC) in the nasal epithelium was also inhibited by GSAE. Treatment with GSAE inhibited the production of MUC5AC in IL-4/IL-13-stimulated primary human nasal epithelial cells through the signal transducer and activator of transcription (STAT)3/STAT6 signaling pathway. These results indicated that GSAE reduces nasal inflammation suggesting that it is a potential treatment option for AR.
Objectives
To identify independent imaging and histopathologic factors that affect washout appearance of hepatocellular carcinoma (HCC) in CT images.
Methods
This retrospective study included 264 ...patients who had undergone surgical resection for treatment-naïve single HCC between January 2014 and December 2015 and had available preoperative multiphasic CT images. Two reviewers evaluated the CT imaging features of HCC using LI-RADS v2018. The “washout” was visually assessed in portal venous or equilibrium phases. Depending on the presence of washout appearance of HCC, all patients were divided into “washout” (
n =
228) and “no washout” (
n =
36) groups. Multivariable logistic regression analysis was used to identify factors associated with the absence of washout appearance of HCC.
Results
A total of 264 HCCs (median size, 2.6 cm) were analyzed. Histologically proven hepatic steatosis (macrovesicular steatosis ≥ 5%) (odds ratio OR, 2.65; 95% confidence interval CI, 1.05–6.74;
p =
0.040), tumor capsule on histopathology (OR, 0.17; 95% CI, 0.06–0.50;
p =
0.001), and mosaic appearance on CT image (OR, 0.34; 95% CI, 0.14–0.85;
p =
0.021) were independent factors associated with the absence of washout appearance of HCC. In 189 patients with available unenhanced CT images, CT-diagnosed hepatic steatosis was also an independent factor for the absence of washout appearance of HCC (OR, 9.26; 95% CI, 3.06–28.02;
p
< 0.001).
Conclusions
Washout appearance of HCC in CT images could be obscured in both histologically proven hepatic steatosis and CT-diagnosed hepatic steatosis, and could be enhanced with tumor capsule on histopathology and mosaic appearance on CT image.
Key Points
•
Hepatic steatosis is an independent factor related to the absence of washout appearance of hepatocellular carcinoma in CT images, in both histologically proven hepatic steatosis and CT-diagnosed hepatic steatosis
.
•
Both histologically proven hepatic steatosis and CT-diagnosed hepatic steatosis have higher odds of absence of washout appearance of hepatocellular carcinoma compared to non-steatotic liver
.
•
Tumor capsule on histopathology and mosaic appearance on CT image are independent factors that enhance the probability that washout appearance of hepatocellular carcinoma is visible
.
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