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1.
Skin Res Technol ; 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33891336

RESUMO

BACKGROUND: Skin aging can be described as a combination of intrinsic and extrinsic aging. Various parameters for evaluating skin characteristics have been proposed. However, an accurate biomarker for skin aging and the relationship between biomarkers and biomechanical parameters of the skin is yet to be explored. MATERIALS AND METHODS: This study included 20 subjects by age. Skin aging was measured using non-invasive devices. Skin tissues were acquired through punch biopsy for immunohistochemistry and qRT-PCR of skin aging biomarkers, and analyzed correlation both, validated their use. RESULTS: Biomechanical properties of skin aging decreased with age. Among the biomarkers previously reported, we found that the expression of Moesin, TXNDC5, RhoGDI, and RSU1 decreased, while that of Vimentin and FABP5 increased with age. Pearson correlation showed that the expression levels of TXNDC5, RhoGDI, RSU1, and Vimentin were significantly correlated with the results of non-invasive measurements. In addition, the expression of TXNDC5, RhoGDI, and RSU1 increased, while that of Vimentin decreased, in skin explants upon treatment with one of the anti-aging compounds, retinoic acid. CONCLUSION: From this study, we identified practical molecular biomarkers of skin aging, TXNDC5, RhoGDI, RSU1, and Vimentin, which correlated with the skin biomechanical properties of skin aging.

2.
Vasc Med ; 26(2): 139-146, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33591894

RESUMO

The role of vascular smooth muscle cells (VSMCs) in vascular calcification, which is related to chronic kidney disease (CKD), has been studied in greater detail in the major arteries relative to the peripheral arteries. We compared the calcifying characteristics of peripheral VSMCs relative to non-pathologic major VSMCs in patients with severe peripheral artery disease (PAD). We isolated peripheral VSMCs from the posterior tibial artery of 10 patients with CKD who underwent below-knee amputation for critical limb ischemia (CLI). Using normal human aortic VSMCs as a control group, we cultured the cells in normal and high phosphate media for 10 days, and subsequently tested by immunofluorescence staining. We compared the calcification levels between the two groups using various assays, tests for cell viability, and scanning electron microscopy. As a result, calcification of pathologic peripheral VSMCs increased significantly with time (p = 0.028) and was significantly higher than that in human aortic VSMCs in calcium assays (p = 0.043). Dead cells in the pathologic VSMC group were more distinct in high phosphate media than in human aortic VSMCs. In conclusion, VSMCs from the peripheral artery of patients with severe CKD and CLI who underwent amputation surgery showed marked calcifying characteristics compared to normal human aortic VSMCs.

3.
J Ethnopharmacol ; 271: 113887, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33539951

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Melicope accedens (Blume) Thomas G. Hartley is a plant included in the family Rutaceae and genus Melicope. It is a native plant from Vietnam that has been used for ethnopharmacology. In Indonesia and Malaysia, the leaves of M. accedens are applied externally to decrease fever. AIM OF THE STUDY: The molecular mechanisms of the anti-inflammatory properties of M. accedens are not yet understood. Therefore, we examined those mechanisms using a methanol extract of M. accedens (Ma-ME) and determined the target molecule in macrophages. MATERIALS AND METHODS: We evaluated the anti-inflammatory effects of Ma-ME in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and in an HCl/EtOH-triggered gastritis model in mice. To investigate the anti-inflammatory activity, we performed a nitric oxide (NO) production assay and ELISA assay for prostaglandin E2 (PGE2). RT-PCR, luciferase gene reporter assays, western blotting analyses, and a cellular thermal shift assay (CETSA) were conducted to identify the mechanism and target molecule of Ma-ME. The phytochemical composition of Ma-ME was analyzed by HPLC and LC-MS/MS. RESULTS: Ma-ME suppressed the production of NO and PGE2 and the mRNA expression of proinflammatory genes (iNOS, IL-1ß, and COX-2) in LPS-stimulated RAW264.7 cells without cytotoxicity. Ma-ME inhibited NF-κB activation by suppressing signaling molecules such as IκBα, Akt, Src, and Syk. Moreover, the CETSA assay revealed that Ma-ME binds to Syk, the most upstream molecule in the NF-κB signal pathway. Oral administration of Ma-ME not only alleviated inflammatory lesions, but also reduced the gene expression of IL-1ß and p-Syk in mice with HCl/EtOH-induced gastritis. HPLC and LC-MS/MS analyses confirmed that Ma-ME contains various anti-inflammatory flavonoids, including quercetin, daidzein, and nevadensin. CONCLUSIONS: Ma-ME exhibited anti-inflammatory activities in vitro and in vivo by targeting Syk in the NF-κB signaling pathway. Therefore, we propose that Ma-ME could be used to treat inflammatory diseases such as gastritis.

4.
Sci Adv ; 7(2)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33523999

RESUMO

Microalgae fuel food webs and biogeochemical cycles of key elements in the ocean. What determines microalgal dominance in the ocean is a long-standing question. Red tide distribution data (spanning 1990 to 2019) show that mixotrophic dinoflagellates, capable of photosynthesis and predation together, were responsible for ~40% of the species forming red tides globally. Counterintuitively, the species with low or moderate growth rates but diverse prey including diatoms caused red tides globally. The ability of these dinoflagellates to trade off growth for prey diversity is another genetic factor critical to formation of red tides across diverse ocean conditions. This finding has profound implications for explaining the global dominance of particular microalgae, their key eco-evolutionary strategy, and prediction of harmful red tide outbreaks.

5.
Pharm Biol ; 59(1): 74-86, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33439064

RESUMO

CONTEXT: Sauropus brevipes Müll. Arg. (Phyllanthaceae) has been used as an effective ingredient in a decoction for the treatment of diarrhoea. However, there was no report on its modulatory role in inflammation. OBJECTIVE: This study investigates anti-inflammatory effect of S. brevipes in various inflammation models. MATERIALS AND METHODS: The aerial part of S. brevipes was extracted with 95% ethanol to produce Sb-EE. RAW264.7 cells pre-treated with Sb-EE were stimulated by lipopolysaccharide (LPS), and Griess assay and PCR were performed. High-performance liquid chromatography (HPLC) analysis, luciferase assay, Western blotting and kinase assay were employed. C57BL/6 mice (10 mice/group) were orally administered with Sb-EE (200 mg/kg) once a day for five days, and peritonitis was induced by an intraperitoneal injection of LPS (10 mg/kg). ICR mice (four mice/group) were orally administered with Sb-EE (20 or 200 mg/kg) or ranitidine (positive control) twice a day for two days, and EtOH/HCl was orally injected to induce gastritis. RESULTS: Sb-EE suppressed nitric oxide (NO) release (IC50=34 µg/mL) without cytotoxicity and contained flavonoids (quercetin, luteolin and kaempferol). Sb-EE (200 µg/mL) reduced the mRNA expression of inducible NO synthase (iNOS). Sb-EE blocked the activities of Syk and Src, while inhibiting interleukin-1 receptor associated kinases (IRAK1) by 68%. Similarly, orally administered Sb-EE (200 mg/kg) suppressed NO production by 78% and phosphorylation of Src and Syk in peritonitis mice. Sb-EE also decreased inflammatory lesions in gastritis mice. DISCUSSION AND CONCLUSIONS: This study demonstrates the inhibitory effect of Sb-EE on the inflammatory response, suggesting that Sb-EE can be developed as a potential anti-inflammatory agent.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33516870

RESUMO

BACKGROUND: Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD). OBJECTIVE: We aimed to investigate the role of NKT cells in AD development, especially in skin. METHODS: Global proteomic and transcriptomic analyses were performed by using skin and blood from human healthy-controls and patients with AD. Levels of CXCR4 and CXCL12 expression in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4+ NKT cells was further evaluated in models of mice with AD by using CXCR4-conditionally deficient or CXCL12 transgenic mice. RESULTS: CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4+ and CD69+. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the liver, spleen, and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4+ NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4+ tissue-resident NKT cells/CXCL12+ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD. CONCLUSIONS: CXCR4+ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.

7.
Cancers (Basel) ; 13(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513833

RESUMO

Transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. In addition, TFEB has various physiological roles such as nutrient sensing, cellular stress responses, and immune responses. However, the precise roles of TFEB in pancreatic cancer growth remain unclear. Here, we show that pancreatic cancer cells exhibit a significantly elevated TFEB expression compared with normal tissue samples and that the genetic inhibition of TFEB results in a significant inhibition in both glutamine and mitochondrial metabolism, which in turn suppresses the PDAC growth both in vitro and in vivo. High basal levels of autophagy are critical for pancreatic cancer growth. The TFEB knockdown had no significant effect on the autophagic flux under normal conditions but interestingly caused a profound reduction in glutaminase (GLS) transcription, leading to an inhibition of glutamine metabolism. We observed that the direct binding of TFEB to the GLS and TFEB gene promotors regulates the transcription of GLS. We also found that the glutamate supplementation leads to a significant recovery of the PDAC growth that had been reduced by a TFEB knockdown. Taken together, our current data demonstrate that TFEB supports the PDAC cell growth by regulating glutaminase-mediated glutamine metabolism.

8.
J Diabetes ; 13(1): 43-53, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32613744

RESUMO

OBJECTIVE: The aim of this study is to compare the gender-different associations between secondhand smoke (SHS) exposure and diabetes in self-reported never smokers verified by cotinine. METHODS: Self-reported never smokers verified by cotinine levels (<50 ng/mL) enrolled in the Kangbuk Samsung Health Study between April 2011 and December 2016 were included for this study. SHS exposure was defined as current exposure to passive smoke indoors at home or workplace. The gender-specific association between SHS exposure and diabetes was assessed using multivariable regression analyses. RESULTS: Of the total 131 724 individuals (mean age 35 years, SD 7.1 years), 66.8% were female, and the prevalence of SHS exposure in the entire population was 22.9%. The prevalence of diabetes in the group exposed to SHS was higher than that in the group unexposed to SHS only in females (1.8% vs 1.2%, P < .001 for females; 2.2% vs 2.2%, P = .956 for males). A significant gender interaction existed for the relationships between SHS exposure and diabetes (P for interaction <.001). The multivariate regression model showed that SHS exposure was significantly associated with diabetes only in females (odds ratio [95% CI], 1.40 [1.20, 1.65] for females; 1.00 [0.85, 1.19] for males). In particular, females with SHS exposure ≥1 hour/day, ≥3 times/week, and ≥10 years showed an increased risk of diabetes by more than 50% compared to those without SHS exposure. CONCLUSIONS: SHS exposure was significantly associated with diabetes in female never smokers with dose-dependent relationship. However, further longitudinal studies are needed to elucidate the gender difference in the incidence of diabetes associated with SHS exposure.

9.
Cell Death Dis ; 11(12): 1034, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277461

RESUMO

Overcoming drug-resistance is a big challenge to improve the survival of patients with epithelial ovarian cancer (EOC). In this study, we investigated the effect of chloroquine (CQ) and its combination with cisplatin (CDDP) in drug-resistant EOC cells. We used the three EOC cell lines CDDP-resistant A2780-CP20, RMG-1 cells, and CDDP-sensitive A2780 cells. The CQ-CDDP combination significantly decreased cell proliferation and increased apoptosis in all cell lines. The combination induced expression of γH2AX, a DNA damage marker protein, and induced G2/M cell cycle arrest. Although the CQ-CDDP combination decreased protein expression of ATM and ATR, phosphorylation of ATM was increased and expression of p21WAF1/CIP1 was also increased in CQ-CDDP-treated cells. Knockdown of p21WAF1/CIP1 by shRNA reduced the expression of γH2AX and phosphorylated ATM and inhibited caspase-3 activity but induced ATM protein expression. Knockdown of p21WAF1/CIP1 partly inhibited CQ-CDDP-induced G2/M arrest, demonstrating that knockdown of p21WAF1/CIP1 overcame the cytotoxic effect of the CQ-CDDP combination. Ectopic expression of p21WAF1/CIP1 in CDDP-treated ATG5-shRNA/A2780-CP20 cells increased expression of γH2AX and caspase-3 activity, demonstrating increased DNA damage and cell death. The inhibition of autophagy by ATG5-shRNA demonstrated similar results upon CDDP treatment, except p21WAF1/CIP1 expression. In an in vivo efficacy study, the CQ-CDDP combination significantly decreased tumor weight and increased expression of γH2AX and p21WAF1/CIP1 in A2780-CP20 orthotopic xenografts and a drug-resistant patient-derived xenograft model of EOC compared with controls. These results demonstrated that CQ increases cytotoxicity in combination with CDDP by inducing lethal DNA damage by induction of p21WAF1/CIP1 expression and autophagy inhibition in CDDP-resistant EOC.

10.
Cell Death Dis ; 11(12): 1072, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318474

RESUMO

Hypoxia-reperfusion injury is one of the major risk factors for neurodegeneration. However, it is unclear whether ischaemic damage in brain microvascular endothelial cells plays roles in neurodegeneration, particularly in the amyloidogenic changes contributing to the development of Alzheimer's disease (AD) pathologies. Therefore, we investigated the roles of hypoxia-reoxygenation (H/R)-induced release of high mobility group box protein 1 (HMGB1), a risk molecule for AD pathogenesis in the ischaemic damaged brain, from human brain microvascular endothelial cells (HBMVECs) in neuronal amyloid-beta (Aß) production. H/R increased nuclear-cytosolic translocation and secretion of HMGB1 in HBMVECs, along with increased permeability and HMGB1-dependent p-c-Jun activation. In addition, H/R increased the expression of Sirtuin 1 (Sirt1), coincident with an increase of intracellular Sirt1-HMGB1 binding in HBMVECs. H/R increased the acetylation of HMGB1 and extracellular secretion, which was significantly inhibited by Sirt1 overexpression. Furthermore, Sirt1 contributed to autophagy-mediated endogenous HMGB1 degradation. More importantly, treatment of neuronal cells with conditioned medium from H/R-stimulated HBMVECs (H/R-CM) activated their amyloidogenic pathways. The neuronal amyloidogenic changes (i.e. increased levels of extracellular Aß40 and Aß42) by H/R-CM from HBMVECs were further increased by Sirt1 inhibition, which was significantly suppressed by neutralization of the HMGB1 in H/R-CM. Collectively, our results suggest that HMGB1 derived from H/R-stimulated HBMVECs contributes to amyloidogenic pathways in neurons playing roles in the pathogenesis of AD, which are regulated by endothelial Sirt1.


Assuntos
Amiloide/metabolismo , Encéfalo/irrigação sanguínea , Células Endoteliais/patologia , Proteína HMGB1/metabolismo , Microvasos/patologia , Neurônios/patologia , Oxigênio/farmacologia , Sirtuína 1/metabolismo , Acetilação/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Permeabilidade da Membrana Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios/metabolismo , Estabilidade Proteica/efeitos dos fármacos
11.
Am J Chin Med ; 48(8): 1895-1913, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33308098

RESUMO

Olea europaea is a beneficial edible plant with a number of biological activities like anti-inflammatory, anti-oxidant, antithrombic, antihyperglycemic, and anti-ischemic activities. The mechanisms behind the antiphotoaging and anti-inflammatory effects of Olea europaea are not fully understood. To investigate how an ethanol extract of Olea europaea (Oe-EE) exerts these effects, we explored its activities in human keratinocytes and dermal fibroblasts. We assessed the anti-oxidant effects of Oe-EE via 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2[Formula: see text]-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assays and measured the expression levels of matrix metalloproteinases (MMPs), cyclooxygenase-2, interleukin (IL)-6, tumor necrosis factor (TNF)-[Formula: see text], and moisturizing factors. Antiphotoaging and anti-inflammatory mechanisms of Oe-EE were explored by assessing signaling molecule activation via immunoblotting. Oe-EE treatment decreased the mRNA expression level of MMPs, cyclooxygenase-2, IL-6, and TNF-[Formula: see text] and restored type I collagen, filaggrin, and sirtuin 1 expression in UVB-irradiated cells. Furthermore, Oe-EE inhibited the activities of several activator protein 1 regulatory enzymes, including extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), and inhibited nuclear factor (NF)-[Formula: see text]B pathway signaling proteins. Therefore, our results indicate that Oe-EE has photoaging-protective and anti-inflammatory effects.

12.
Psychiatry Res Neuroimaging ; 307: 111226, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33249305

RESUMO

Impaired social cue perception such as emotional recognition is a prominent feature in patients with schizophrenia, adversely affecting psychosocial outcomes and worsening clinical manifestations of the disease. However, few structural neuroimaging studies have investigated both facial emotion recognition and emotion intensity recognition in schizophrenia. Ninety patients with schizophrenia spectrum psychosis and fifty healthy controls underwent structural magnetic resonance imaging. The gray matter volumes of emotion recognition areas such as the bilateral caudal anterior cingulate cortex, rostral anterior cingulate cortex, fusiform gyrus, insula, amygdala, and hippocampus, were compared between patients and controls. Emotional recognition levels and symptom severities were examined. Group analysis showed that the gray matter volumes of the patients were significantly smaller in left hippocampus and fusiform gyrus compared with healthy controls. A correlation analysis revealed that larger left fusiform gyrus volume was associated with better facial emotion recognition and emotional intensity recognition in patients with schizophrenia spectrum psychosis. Additionally, left fusiform gyrus volumes showed a significant negative correlation with the negative symptom scores at baseline. These findings suggest that gray matter abnormalities in the left fusiform gyrus are associated with impaired social emotion recognition and severity of negative symptoms at baseline in patients with schizophrenia spectrum psychosis.

13.
Sci Rep ; 10(1): 20250, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33219294

RESUMO

The association between angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) and the risk of mortality in hospitalized patients with severe coronavirus disease 2019 (COVID-19) was investigated. This retrospective cohort study was performed in all hospitalized patients with COVID-19 in tertiary hospitals in Daegu, Korea. Patients were classified based on whether they received ACE-I or ARB before COVID-19 diagnosis. The analysis of the primary outcome, in-hospital mortality, was performed using the Cox proportional hazards regression model. Of 130 patients with COVID-19, 30 (23.1%) who received ACE-I or ARB exhibited an increased risk of in-hospital mortality (adjusted hazard ratio, 2.20; 95% confidence interval [CI], 1.10-4.38; P = 0.025). ACE-I or ARB was also associated with severe complications, such as acute respiratory distress syndrome (ARDS) (adjusted odds ratio [aOR], 2.58; 95% CI, 1.02-6.51; P = 0.045) and acute kidney injury (AKI) (aOR, 3.06; 95% CI, 1.15-8.15; P = 0.026). Among the patients with ACE-I or ARB therapy, 8 patients (26.7%) used high equivalent doses of ACE-I or ARB and they had higher in-hospital mortality and an increased risk of ARDS and AKI (all, P < 0.05). ACE-I or ARB therapy in patients with severe COVID-19 was associated with the occurrence of severe complications and increased in-hospital mortality. The potentially harmful effect of ACE-I or ARB therapy may be higher in patients who received high doses.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33143335

RESUMO

(1) Background: This study aims to investigate the impact of emotional labor and workplace violence on sleep disturbance, depression, and health status in workers. (2) Methods: Data from 34,742 participants of the 2011-2014 Korean Working Conditions Survey were included in this study. We compared the incidence of sleep disturbance, depression, and health status according to emotional labor and workplace violence and used logistic regression to analyze factors that affect health status. (3) Results: Emotional laborers were more likely to experience sleep disturbance, depression and anxiety, and muscle pain. Workers who have experienced workplace violence were more likely to experience depression and anxiety, abdominal pain, and sleep disturbance. (4) Conclusion: Emotional labor and workplace violence have a grave impact on physical and mental health, with particularly greater effects on mental health. In addition, workplace violence has a greater health impact than emotional labor. The findings of this study suggest the need to implement programs that stabilize and heal workers who have experienced emotional labor and to enforce regulations and policies to protect workers from verbal and physical abuse.

15.
Foods ; 9(11)2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33147777

RESUMO

Rubus coreanus Miquel (R. coreanus) is a unripen fruit of black raspberry native to eastern Asia. It is used as traditional oriental medicine and supplementary foods for centuries. Previous studies have shown that the R. coreanus extract (RCE) and its main constitute ellagic acid possess diverse biological activities. However, the effects of RCE on antitumor immunity and T cell function were not fully understood. The present study describes the anti-tumor effect of RCE in humanized PD-1 mice by blocking PD-1/PD-L1 interaction. Competitive enzyme-linked immunosorbent assay (ELISA) and pull down assay were performed to elucidate the binding properties of RCE in vitro. Cellular PD-1/PD-L1 blockade activities were measured by T cell receptor (TCR)-induced nuclear factor of activated T cells-luciferase activity in co-cultured cell models with PD-1/NFAT Jurkat and PD-L1/aAPC CHO-K1 cells. The in vivo efficacy of RCE was confirmed in humanized PD-1 mice bearing MC38 colorectal tumor. RCE and ellagic acid dose-dependently block the binding of PD-1 to PD-L1. Moreover, oral administration of RCE showed the potent anti-tumor activity similar to anti-PD-1 antibody. The present study suggests that RCE possesses potent anti-tumor effect via PD-1/PD-L1 blockade, and ellagic acid is the main compound in RCE. Thus, we provide new aspects of RCE as an immunotherapeutic agent.

16.
Front Immunol ; 11: 598556, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224152

RESUMO

Immune checkpoint inhibitors, increasingly used to treat malignant tumors, are revolutionizing cancer treatment by improving the patient survival expectations. Despite the high antitumor efficacy of antibody therapeutics that bind to PD-1/PD-L1, study on small molecule-based PD-1/PD-L1 inhibitors is required to overcome the side effects of antibody therapeutics caused by their size and affinity. Herein, we investigated antitumor potential of Salvia plebeia R. Br. extract (SPE), which has been used as a traditional oriental medicine and food in many countries, and its components by the blockade of PD-1/PD-L1 interaction. SPE and its component cosmosiin effectively blocked the molecular interaction between PD-1 and PD-L1. SPE also inhibited tumor growth by increasing CD8+ T-cells in the tumor through the activation of tumor-specific T-cells in a humanized PD-1 mouse model bearing hPD-L1 knock-in MC38 colon adenocarcinoma tumor. This finding presents a preclinical strategy to develop small molecule-based anticancer drugs targeting the PD-1/PD-L1 immune checkpoint pathway.

17.
Oxid Med Cell Longev ; 2020: 8824934, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204399

RESUMO

Antigenic mismatch can cause influenza vaccines to be ineffective, and influenza viruses resistant to antiviral drugs are rising. Thus, development of antiviral agents against these viruses is an immediate need. Rhus verniciflua (RVS) has long been used in herbal medicine and as a nutritional supplement. The effect of RVS and its components on influenza virus has not, however, been reported. We found that RVS treatment significantly reduced viral replication when evaluated with green fluorescent protein- (GFP-) tagged virus (influenza A virus, A/PR/8/34-GFP) in Madin-Darby canine kidney (MDCK) cells. RVS showed significant inhibition of neuraminidase from A/PR/8/34. Subsequently, three fractions were prepared from an ethanolic crude extract of RVS. In vitro assays indicated that an ethyl acetate fraction (RVSE) was more potent than H2O and CHCl3 fractions. RVSE significantly suppressed influenza virus infection in MDCK cells via neuraminidase inhibition. Additionally, RVSE treatment inhibited expression of several virus proteins and decreased mortality of mice exposed to influenza A/PR/8/34 by 50% and reduced weight loss by 11.5%. Active components in RVSE were isolated, and 5-deoxyluteolin (5) and sulfuretin (7) demonstrate the highest neuraminidase inhibitory activity against influenza A virus. RVS, RVSE, and their constituents may be useful for the development of anti-influenza agents.

18.
Biochem Pharmacol ; 182: 114264, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33035507

RESUMO

3-Deazadenosine (3-DA) is a general methylation inhibitor that depletes S-adenosylmethionine, a methyl donor, by blocking S-adenosylhomocysteine hydrolase (SAHH). In this study, we investigated the inhibitory activity and molecular mechanisms of 3-DA in inflammatory responses. 3-DA suppressed the secretion of inflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide-treated RAW264.7 cells and phorbol 12-myristate 13-acetate (PMA)-differentiated U937 cells. It also reduced mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, interleukin-1ß (IL-1 ß), and IL-6, indicating that 3-DA has anti-inflammatory properties in murine and human macrophages. Moreover, 3-DA strongly blocked AP-1 and NF-κB luciferase activity under PMA-, MyD88-, and TRIF-stimulated conditions and decreased the translocation of c-Jun, c-Fos, p65, and p50 into the nucleus. In addition, the p-ERK level in AP-1 signaling and the p-IκBα level in NF-kB signaling were diminished by 3-DA treatment. Interestingly, 3-DA did not alter the phosphorylation of MEK1/2, an ERK modulator, or IKKα/ß, an IκBα regulator. Instead, 3-DA prevented MEK1/2 and IKKα/ß from combining with ERK and IκBα, respectively, and directly suppressed MEK1/2 and IKKα/ß kinase activity. These results indicate that MEK1/2 and IKKα/ß are direct targets of 3-DA. In addition, suppression of SAHH by siRNA or treatment with adenosine dialdehyde, another SAHH inhibitor, showed inhibitory patterns against p-ERK and IκBα similar to those of 3-DA. Taken together, this study demonstrates that 3-DA inhibits AP-1 and NF-κB signaling by directly blocking MEK1/2 and IKKα/ß or indirectly mediating SAHH, resulting in anti-inflammatory activity.

19.
Artigo em Inglês | MEDLINE | ID: mdl-33043479

RESUMO

PDE4 inhibitors are involved in anti-inflammatory and immunomodulatory responses. Recently, they have been getting attention as a new class of drugs treating inflammatory airway diseases. The T lymphocyte is a major cell type present in the inflammatory infiltrate in the airway wall in patients with chronic obstructive pulmonary disease (COPD), and a previous study found that treatment with a PDE4 inhibitor significantly suppressed T cell proliferation. However, the mechanism of action of PDE4 inhibitors has not been elucidated. The present study aimed to investigate major signal transduction pathways of T lymphocyte and identify the phase, during which PDE4 inhibitors affect T cell proliferation. Isolated splenic CD4+ T cells were grown under stimulation with an anti-CD3/CD28 antibody, and/or treated with roflumilast-n-oxide (RNO). A western blot assay was performed using major antibodies including anti-p-38, anti-p-PI3K, anti-p-JNK, anti-p-ERK 1/2, anti-NFAT1 (NFATc2), and anti-NF-kB antibodies. Additional experiments conducted on the pathway showed significant change following RNO treatment, thus providing further evidence for signal transduction pathway concerning PDE4 inhibitors. T cell proliferation was suppressed by RNO treatment. In the pathways involved in T cell proliferation, only expression of anti-NFAT1 antibody was suppressed by RNO treatment. In additional experiments on the NFAT pathway, the very first phase (TCR signalling) remained unchanged on treatment with RNO, but RNO treatment increased IP3R expression and suppressed calcineurin activity. Calcineurin activity, reduced by RNO, increased on treatment with an IP3 receptor agonist. PED4 inhibitor, roflumilast is speculated to suppress T cell proliferation by interfering with IP3-IP3R binding to inhibit calcium emission, blocking pathway activation from this phase onward, eventually decreasing the level of a growth factor for T cell proliferation, IL-2.

20.
Thorax ; 75(11): 982-993, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33023995

RESUMO

BACKGROUND: Epithelial to mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP). Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood. OBJECTIVE: We sought to evaluate the role of Wnt signaling in EMT of CRSwNP using a murine nasal polyp (NP) model and human tissues. METHODS: Inflammatory markers and EMT-related molecules were evaluated in NP models using adenomatosis polyposis coli (Apc)Min/+ mice with activated Wnt signaling and NP models treated with Wnt signaling inhibitor, indocyanine green-001 (ICG-001). EMT markers and Wnt signaling-associated mediators were analysed using human sinonasal tissues from control subjects and CRSwNP patients. RESULTS: ApcMin/+ mice-induced NPs exhibited more frequent polypoid lesions and upregulation of Wnt-related molecules, including nuclear ß-catenin, WNT3A and cyclin D1. Markers of EMT were significantly overexpressed in the ApcMin/+ NP mice (p<0.001 for E-cadherin and α-smooth muscle actin), and interleukin (IL)-17A+ cells and neutrophilic infiltration were increased in ApcMin/+ NP mice (p<0.001). Inhibition of Wnt signaling via ICG-001 resulted in significantly decreased nasal polypoid lesions (p<0.001), EMT-related markers (p=0.019 for E-cadherin and p=0.002 for vimentin) and the mRNA levels of IL-4 (p<0.001) and IL-17A (p=0.004) compared with the positive control group. Finally, nuclear ß-catenin (p=0.042) was significantly increased compared with the control, and the expression levels of Wnt ligands and receptors were upregulated in human NP tissues (p=0.045 for WNT3A and p=0.042 for FZD2), suggesting increased Wnt signaling and EMT in CRSwNP. CONCLUSION: Wnt signaling may contribute to the pathogenesis of NPs through EMT. Therefore, inhibition of Wnt signaling may be a potential therapeutic strategy for patients with CRSwNP.

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