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[This corrects the article DOI: 10.3389/fcvm.2022.813710.].
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Plenty of evidence has recently shown that various inflammatory activities at the local tissue, organ, or even the whole body (systemic) level are strongly linked to many life-threatening chronic diseases, most notably various cancers. However, only very limited information is available for making good use of our supporting immune-modulatory therapeutics for the treatment of cancers. This may result from a lack of studies on specific remedies for efficacious control or modulatory suppression of inflammation-related cancerous diseases. Our group and laboratories were fortunate to have initiated and consistently pursued an integrated team-work program project, aimed at investigating selected medicinal herbs and the derived, purified phytochemical compounds. We focused on the study of key and specific immune-signaling mechanisms at the cellular and molecular levels. We were fortunate to obtain a series of fruitful research results. We believe that our key findings reported herein may be helpful for proposing future thematic and integrated research projects that aim to develop future phytochemical drugs against cancers. The mechanisms of the cellular and molecular systems involved in inflammation are becoming increasingly recognized as keystones for the development of future therapeutic approaches for many chronic and cancerous diseases. Recently, the immune checkpoint inhibitors such as antibodies against PD-1 and/or PD-L1 have been shown to be too expensive for general clinical use, and their effects far from optimal, often showing little or no effect or only short-term efficacy. These results point to the need for developing future immune-regulatory or modulatory therapeutics.
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Vacinas Anticâncer , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Microambiente TumoralRESUMO
Purpose: This study is to assess the diagnostic value of noninvasive regional myocardial work (MW) by echocardiography for detecting the functional status of coronary stenosis using fractional flow reserve (FFR) as a standard criterion. Methods: A total of 84 consecutive patients were included in this study, among which 92 vessels were identified with ≥50% stenosis confirmed by invasive coronary angiography. Patients were investigated by invasive FFR and transthoracic echocardiography. Regional MW indices including myocardial work index (MWI), myocardial constructive work (MCW), myocardial wasted work, and myocardial work efficiency were calculated. Results: MWI and MCW were significantly impaired in the FFR ≤ 0.75 group compared with the FFR > 0.75 group (both p < 0.01). There were significant positive associations between MWI and MCW with FFR. In total group, MWI <1,623.7 mmHg% [sensitivity, 78.4%; specificity, 72.2%; area under the curve value, 0.768 (0.653-0.883)] and MCW <1,962.4 mmHg% [77.0%; 72.2%; 0.767 (0.661-0.872)], and in single-vessel subgroup, MWI <1,412.1 mmHg% [93.5%; 63.6%; 0.808 (0.652-0.965)] and MCW <1,943.3 mmHg% [(84.8%; 72.7%; 0.800 (0.657-0.943)] were optimal to detect left ventricular segments with an FFR ≤ 0.75. MWI and MCW significantly increased after percutaneous coronary intervention in 13 cases. Conclusion: In patients with coronary artery disease, especially those with single-vessel stenosis, the regional MW measured by echocardiography exhibited a good diagnostic value in detecting significant myocardial ischemia compared to the standard FFR approach.
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BACKGROUND: EGFR mutational testing is crucial for advanced non-squamous NSCLC. PAP is a sensitive and selective method to detect rare mutations. METHODS: Eighty-five patients with non-squamous NSCLC were enrolled in this study. A set of paired plasma samples from each patient were collected and detected by PAP and ARMS. RESULTS: Of 85 paired samples, 78.8% (67/85) presented the same mutational status by the two methods. There was no statistically significant difference between the mutation frequencies in plasma samples detected with PAP and ARMS (p = 0.096). CONCLUSIONS: PAP technology appears to be an alternative choice with relatively high sensitivity for the detection of plasma EGFR mutations.
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Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA/métodos , Neoplasias Pulmonares/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/sangue , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
The incidence of inflammatory bowel disease (IBD) has markedly increased. Our research findings during the past showed that medicinal plant extracts and the derived phytochemical components from Wedelia chinensis (WC) can have strong anti-colitis activities. Here, we further identified the key component phytochemicals from active fractions of different WC preparations (WCHA) that are responsible for the protective effect of WCHA in colitis mice. Of the 3 major compounds (wedelolactone, luteolin and apigenin) in this fraction, luteolin had the highest anti-inflammatory effect in vivo. Using a next-generation sequencing (NGS) (e.g., RNA-seq) system to analyze the transcriptome of colorectal cells/tissues in mice with dextran sulfate sodium (DSS)-induced colitis with/without phytochemicals treatment, luteolin was found to strongly suppress the DSS-activated IL-17 pathway in colon tissue. In addition, co-treatment with wedelolactone and luteolin had a synergistic effect on the expression level of some IL-17 pathway-related genes. Interestingly, our NGS analyses also indicated that luteolin and wedelolactone can specifically suppress the expression of NLRP3 and NLRP1. Using a 3-dimensional cell co-culture system, we further demonstrated that luteolin could efficiently suppress NLRP3 expression via disruption of IL-17A signaling in inflamed colon tissue, which also indicates the pharmacological potential of luteolin and wedelolactone in treating IBD.
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Colite/genética , Perfilação da Expressão Gênica , Interleucina-17/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Wedelia/química , Células 3T3 , Doença Aguda , Processamento Alternativo/genética , Animais , Colite/patologia , Colo/patologia , Cumarínicos/farmacologia , Sulfato de Dextrana , Retroalimentação Fisiológica , Inflamassomos/metabolismo , Interleucina-17/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Luteolina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologiaRESUMO
[This corrects the article DOI: 10.18632/oncotarget.9660.].
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The difficulty of long-term management has produced a high rate of failure for obesity patients. Therefore, improving the efficacy of current obesity treatment is a significant goal. We hypothesized that combining a probiotic Lactobacillus mali APS1 intervention with dieting could improve the efficacy of obesity and hepatic steatosis treatment compared to dieting alone. Mice were fed a high-fat diet for 6 weeks and then treated with: saline + normal diet and APS1 + normal diet (NDAPS1) for 3 weeks. NDAPS1 accelerated body weight loss and reduced caloric intake and fat accumulation. The fecal microbiome showed that accelerating weight loss by NDAPS1 resulted in restoring intestinal microbiota toward a pre-obese state, with alteration of specific changes in the obesity-associated bacteria. APS1 manipulated the gut microbiome's obesity-associated metabolites, followed by regulation of lipid metabolism, enhancement of energy expenditure and inhibition of appetite. The specific hepatic metabolites induced by the APS1-manipulated gut microbiome also contributed to the amelioration of hepatic steatosis. Our results highlighted a possible microbiome and metabolome that contributed to accelerating weight loss following treatment with a combination of APS1 and dieting and suggested that probiotics could serve as a potential therapy for modulating physiological function and downstream of the microbiota.
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Dieta , Microbioma Gastrointestinal , Lactobacillus , Obesidade/dietoterapia , Tecido Adiposo/patologia , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Ingestão de Energia , Hormônios/metabolismo , Espectrometria de Massas , Metabolômica/métodos , Camundongos , Obesidade/metabolismo , Obesidade/patologia , Probióticos/administração & dosagem , Redução de PesoRESUMO
SCOPE: Non-alcoholic fatty liver disease (NAFLD) is a common disease that is concomitant with obesity, resulting in increased mortality. To date, the efficiency of NAFLD treatment still needs to be improved. Therefore, we aimed to evaluate the effect of Lactobacillus mali APS1, which was isolated from sugary kefir, on hepatic steatosis in rats fed a high-fat diet (HFD). METHODS AND RESULTS: Sprague Dawley rats were fed a control diet, a HFD with saline, and a HFD with APS1 intervention by gavage daily for 12 weeks. The results showed that APS1 significantly reduced body weight and body weight gain in HFD-fed rats. APS1 reduced hepatic lipid accumulation by regulating SIRT-1/PGC-1α/SREBP-1 expression. Moreover, APS1 increased hepatic antioxidant activity by modulating Nrf-2/HO-1 expression. Notably, APS1 manipulated the gut microbiota, resulting in increasing proportions of the phylum Bacteroidetes/Firmicutes and reducing the abundance of specific NAFLD-associated bacteria. CONCLUSION: These results suggested that APS1 ameliorated hepatic steatosis by modulating lipid metabolism and antioxidant activity via manipulating specific NAFLD-associated gut microbiota in vivo.
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Fármacos Antiobesidade/uso terapêutico , Kefir/microbiologia , Lactobacillus/crescimento & desenvolvimento , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/prevenção & controle , Prebióticos/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Fármacos Antiobesidade/administração & dosagem , Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fator de Transcrição de Proteínas de Ligação GA/genética , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Microbioma Gastrointestinal , Regulação da Expressão Gênica , Lactobacillus/isolamento & purificação , Lipotrópicos/administração & dosagem , Lipotrópicos/uso terapêutico , Fígado/imunologia , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Obesidade/metabolismo , Obesidade/microbiologia , Obesidade/fisiopatologia , Estresse Oxidativo , Distribuição Aleatória , Ratos Sprague-Dawley , Sirtuína 1/genética , Sirtuína 1/metabolismo , Aumento de PesoRESUMO
Programmed necrosis, necroptosis, is considered to be a highly immunogenic activity, often mediated via the release of damage-associated molecular patterns (DAMPs). Interestingly, enhanced macroautophagic/autophagic activity is often found to be accompanied by necroptosis. However, the possible role of autophagy in the immunogenicity of necroptotic death remains largely obscure. In this study, we investigated the possible mechanistic correlation between phytochemical shikonin-induced autophagy and the shikonin-induced necroptosis for tumor immunogenicity. We show that shikonin can instigate RIPK1 (receptor [TNFRSF]-interacting serine-threonine kinase 1)- and RIPK3 (receptor-interacting serine-threonine kinase 3)-dependent necroptosis that is accompanied by enhanced autophagy. Shikonin-induced autophagy can directly contribute to DAMP upregulation. Counterintuitively, among the released and ectoDAMPs, only the latter were shown to be able to activate the cocultured dendritic cells (DCs). Interruption of autophagic flux via chloroquine further upregulated ectoDAMP activity and resultant DC activation. For potential clinical application, DC vaccine preparations treated with tumor cells that were already pretreated with chloroquine and shikonin further enhanced the antimetastatic activity of 4T1 tumors and reduced the effective dosage of doxorubicin. The enhanced immunogenicity and vaccine efficacy obtained via shikonin and chloroquine cotreatment of tumor cells may thus constitute a compelling strategy for developing cancer vaccines via the use of a combinational drug treatment.
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Alarminas/metabolismo , Apoptose , Autofagia , Vigilância Imunológica , Regulação para Cima , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cloroquina/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Imunização , Camundongos Endogâmicos BALB C , Modelos Biológicos , Naftoquinonas/farmacologia , Necrose , Metástase Neoplásica , Regulação para Cima/efeitos dos fármacosRESUMO
Phytochemicals or their derived compounds are being increasingly recognized as potentially potent complementary treatments for cancer. Among them, some phytochemicals are being actively evaluated for use as adjuvants in anticancer therapies. For instance, shikonin and hypericin were found to induce immunogenic cell death of specific cancer cells, and this effect was able to further activate the recognition activity of tumor cells by the host immune system. On the other hand, some derivatives of phytochemicals, such as dihydrobenzofuran lignan (Q2-3) have been found to induce the secretion of an endogenous anticancer factor, namely IL-25, from non-malignant cells. These findings suggest that phytochemicals or their derivatives confer a spectrum of different pharmacological activities, which contrasts with the current cytotoxic anticancer drugs commonly used in clinics. In this review, we have collected together pertinent information from recent studies about the biochemical and cellular mechanisms through which specific phytochemicals regulate target immune systems in defined tumor microenvironments. We have further highlighted the potential application of these immunotherapeutic modifiers in cell-based cancer vaccine systems. This knowledge provides useful technological support and know how for future applications of phytochemicals in cancer immunotherapy.
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Myeloid-derived suppressor cells (MDSCs) are implicated in the promotion of tumor metastasis by protecting metastatic cancerous cells from immune surveillance and have thus been suggested as novel targets for cancer therapy. We demonstrate here that oral feeding with polyacetylenic glycosides (BP-E-F1) from the medicinal plant Bidens pilosa effectively suppresses tumor metastasis and inhibits tumor-induced accumulation of granulocytic (g) MDSCs, but does not result in body weight loss in a mouse mammary tumor-resection model. BP-E-F1 is further demonstrated to exert its anti-metastasis activity through inhibiting the differentiation and function of gMDSCs. Pharmacokinetic and mechanistic studies reveal that BP-E-F1 suppresses the differentiation of gMDSCs via the inhibition of a tumor-derived, G-CSF-induced signaling pathway in bone marrow cells of test mice. Taken together, our findings suggest that specific plant polyacetylenic glycosides that target gMDSC differentiation by communicating with bone marrow cells may hence be seriously considered for potential application as botanical drugs against metastatic cancers.
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Células Supressoras Mieloides/efeitos dos fármacos , Metástase Neoplásica/prevenção & controle , Compostos Fitoquímicos/farmacologia , Poli-Inos/farmacologia , Animais , Bidens/química , Diferenciação Celular , Linhagem Celular Tumoral , Fator Estimulador de Colônias de Granulócitos/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Transgênicos , Células Supressoras Mieloides/citologiaRESUMO
Immunogenic cell death (ICD) of tumor cells occurs via various pathways that activate immune cell systems against cancer. Previous studies have demonstrated that shikonin (SK), a plant secondary metabolite, can confer strong pharmacological activities that activate ICD and strong immunogenicity of tumor cells. However, the exact hierarchical regulatory mechanisms including the molecular targets of SK-activated immunogenicity are still unknown. Here, the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was revealed to serve as a specific protein target for SK. This binding plays a key role in SK-stimulated ICD activity and the suppression of post-transcriptional mRNA processing, including nuclear export activity of newly synthesized mRNAs in mammary carcinoma cells in vitro. Moreover, it also mechanistically mediates the anti-metastatic effect of a tumor cell lysate (TCL) vaccine, which can be readily generated from SK-treated 4T1 tumor cells (SK-TCL), and the derived tumor-immunogenicity of SK-TCL-treated dendritic cells in vivo. Together, the identification of hnRNPA1 as the intracellular molecular target provides compelling pharmacology-based knowledge for the potential clinical use of SK-induced immunogenicity. In addition, SK may also serve as a potent suppressor that interferes with specific post-transcriptional activities, a mechanism which may be useful for exploitation in cancer therapeutics.
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Antineoplásicos/uso terapêutico , Apoptose/imunologia , Neoplasias da Mama/terapia , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Naftoquinonas/uso terapêutico , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , Animais , Antineoplásicos/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Feminino , Ribonucleoproteína Nuclear Heterogênea A1/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Naftoquinonas/imunologia , RNA Mensageiro/metabolismo , Espectrometria de Massas em Tandem , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities.
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Neoplasias da Mama/metabolismo , Fibroblastos/metabolismo , Interleucinas/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Células 3T3 , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Lignanas/química , Lignanas/farmacologia , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Metástase Neoplásica , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In our continued focus on 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) analogs, we synthesized a novel series of 3,9-substituted α-carboline derivatives and evaluated the new compounds for antiproliferactive effects. Structure activity relationships revealed that a COOCH3 or CH2OH group at position-3 and substituted benzyl group at position-9 of the α-carboline nucleus were crucial for maximal activity. The most active compound, 11, showed high levels of cytotoxicity against HL-60, COLO 205, Hep 3B, and H460 cells with IC50 values of 0.3, 0.49, 0.7, and 0.8 µM, respectively. The effect of compound 11 on the cell cycle distribution demonstrated G2/M arrest in COLO 205 cells. Furthermore, mechanistic studies indicated that compound 11 induced apoptosis by activating death receptor and mitochondria dependent apoptotic signaling pathways in COLO 205 cells. The new 3,9-substituted α-carboline derivatives exhibited excellent anti-proliferative activities, and compound 11 can be used as a promising pro-apoptotic agent for future development of new antitumor agents.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias Colorretais/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Reto/efeitos dos fármacos , Reto/patologia , Relação Estrutura-AtividadeRESUMO
Bidens pilosa, a medicinal herb worldwide, is rich in bioactive polyynes. In this study, by using high resolution 2-dimensional gel electrophoresis coupled with mass spectrometry analysis, as many as 2000 protein spots could be detected and those whose expression was specifically up- or downregulated in Jurkat T cells responsive to the treatment with 2-ß-D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetrayne (GHTT) can be identified. GHTT treatment can upregulate thirteen proteins involved in signal transduction, detoxification, metabolism, energy pathways, and channel transport in Jurkat cells. Nine proteins, that is, thioredoxin-like proteins, BH3 interacting domain death agonist (BID protein involving apoptosis), methylcrotonoyl-CoA carboxylase beta chain, and NADH-ubiquinone oxidoreductase, were downregulated in GHTT-treated Jurkat cells. Further, bioinformatics tool, Ingenuity software, was used to predict signaling pathways based on the data obtained from the differential proteomics approach. Two matched pathways, relevant to mitochondrial dysfunction and apoptosis, in Jurkat cells were inferred from the proteomics data. Biochemical analysis further verified both pathways involving GHTT in Jurkat cells. These findings do not merely prove the feasibility of combining proteomics and bioinformatics methods to identify cellular proteins as key players in response to the phytocompound in Jurkat cells but also establish the pathways of the proteins as the potential therapeutic targets of leukemia.
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Suppression of tumor metastasis is a key strategy for successful cancer interventions. Previous studies indicated that rapamycin (sirolimus) may promote tumor regression activity or enhance immune response against tumor targets. However, rapamycin also exhibits immunosuppressant effects and is hence used clinically as an organ transplantation drug. We hypothesized that the immunosuppressive activities of rapamycin might also negatively mediate host immunity, resulting in promotion of tumor metastasis. In this study, the effects of rapamycin and phytochemical shikonin were investigated in vitro and in vivo in a 4T1 mouse mammary tumor model through quantitative assessment of immunogenic cell death (ICD), autophagy, tumor growth and metastasis. Tumor-bearing mice were immunized with test vaccines to monitor their effect on tumor metastasis. We found that intraperitoneal (ip) administration of rapamycin after a tumor-resection surgery drastically increased the metastatic activity of 4T1 tumors. Possible correlation of this finding to human cancers was suggested by epidemiological analysis of data from Taiwan's National Health Insurance Research Database (NHIRD). Since our previous studies showed that modified tumor cell lysate (TCL)-pulsed, dendritic cell (DC)-based cancer vaccines can effectively suppress metastasis in mouse tumor models, we assessed whether such vaccines may help offset this rapamycin-promoted metastasis. We observed that shikonin efficiently induced ICD of 4T1 cells in culture, and DC vaccines pulsed with shikonin-treated TCL (SK-TCL-DC) significantly suppressed rapamycin-enhanced metastasis and Treg cell expansion in test mice. In conclusion, rapamycin treatment in mice (and perhaps in humans) promotes metastasis and the effect may be offset by treatment with a DC-based cancer vaccine.
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Vacinas Anticâncer/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Sirolimo/efeitos adversos , Adulto , Animais , Autofagia/efeitos dos fármacos , Autofagia/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Naftoquinonas/efeitos adversos , Metástase Neoplásica , Neoplasias/induzido quimicamente , Neoplasias/epidemiologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Adulto JovemRESUMO
BACKGROUND: The tumor cell lysate-pulsed, dendritic cell (DC)-based cancer vaccine approaches are being actively evaluated for application to cancer immunotherapy, hopefully at a personalized medicine base. There is apparently an emerging technical problem however, the lack of highly efficacious potency in activation of patient's DCs for T-cell priming and the associated process for presenting tumor immunogenicity. METHODS: One strategy to address this is to consider the manipulation of the tumor immunogenic cells death (ICD) complex ex-vivo for maximal activation of DC efficacy. In our previous study we showed that phytochemical shikonin (SK) can drastically enhance ICD activity in mouse tumor cells treated ex-vivo, and the resultant tumor cell lysate (TCL) can effectively augment such SK-TCL pulsed DC vaccine activity in vivo in anti-tumor activities. In this study, we investigated the specifics and the multi-functional effects of various damaged associated molecular pattern (DAMP) components of the ICD complex for their participation, roles and potential cross talks in activating DCs, as measured by five different functional assays. RESULTS: Among three DAMPs tested, HSP70 and CRT mediate a key role in SK-TCL-induced DC immunity for both CD4(+) and CD8(+) T cell proliferations in vitro. HSP70 is the most important component, followed by CRT, then HMGB1 in facilitating DC immunity on suppressing metastasis of mouse 4 T1 mammary tumors and prolonging survival in test mice. Only HSP70, but not CRT or HMGB1, is effective for the suppression of both granulocytic and monocytic MDSC populations in vivo. Both HSP70 and HMGB1, but not CRT, are essential in activating the expression of three key ICD molecules-associated receptors on test DCs. Each of the three test ICD proteins can exhibit a distinguishable pattern in stimulating the expression of four key chemokines in test DCs. CONCLUSION: Our findings on the differential roles or effect of various ICD components in activating vaccinated DCs may help formulate new strategies for future cancer vaccine designs.
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Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Imunoterapia , Melanoma Experimental/imunologia , Naftoquinonas/administração & dosagem , Animais , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Proteína HMGB1/genética , Proteína HMGB1/imunologia , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Melanoma Experimental/genética , Melanoma Experimental/prevenção & controle , Melanoma Experimental/terapia , Camundongos , Medicina de Precisão , Linfócitos T/imunologiaRESUMO
Bullous pemphigoid (BP), a common autoimmune skin disease, is associated with IgG autoantibodies against the hemidesmosomal proteins, BP180 and BP230. In addition to IgG, IgE has been shown to play a role in the disease. However, the association between disease activity and IgE specific to the NC16A domain of BP180 in blister fluid remains unclear. Our objective was to evaluate the correlation between BP disease activity and BP180 NC16A-specific IgE sera and blister fluid titers, and to analyze changes during treatment. We evaluated the levels of anti-BP180 IgE autoantibodies in the sera and blister fluids of 37 BP patients using an Enzyme-linked immunosorbent assay. We also observed changes in the levels of these antibodies in 2 BP patients at 4 or 5 different time points (day 0 when the patient first visited our hospital, day 5, day 14, day 39 and day 62 for patient 1; day 0, day 4, day 8 and day 17 for patient 2). We also collected extra serum samples from the 2 patients when the disease was controlled (blister disappeared) (day 85, day 104 and day 146 for patient 1 and day 123, day 158 and day 189 for the other patient). IgE anti-BP180 antibodies were detected in the serum of 72.97 % of the patients. There was no correlation between disease activity scores and BP180 NC16A IgE titers in serum (r = -0.077, p > 0.05) or in blister fluid (r = 0.262, p > 0.05). The levels of the autoantibody in serum were positively correlated with that in blister fluid (r = 0.6651, p < 0.001); however, the levels continued to rise despite effective control of the disease in the initial two to 6 weeks of diagnosis. The level of this autoantibody reached a peak on day 39 for patient 1 and on day 17 for patient 2 although the systemic and topical medication of steroid had controlled the disease process effectively. We conclude that levels of anti-BP180 NC16A IgE are higher in the sera than blister fluids. These levels could generally reflect disease severity throughout the course of the disease, but not in the early stages of medication.
Assuntos
Anticorpos/sangue , Anticorpos/imunologia , Autoantígenos/imunologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/imunologia , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoimunidade/imunologia , Vesícula/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Penfigoide Bolhoso/patologia , Estrutura Terciária de Proteína , Colágeno Tipo XVIIRESUMO
For the development of "medical foods" and/or botanical drugs as defined USA FDA, clear and systemic characterizations of the taxonomy, index phytochemical components, and the functional or medicinal bioactivities of the reputed or candidate medicinal plant are needed. In this study, we used an integrative approach, including macroscopic and microscopic examination, marker gene analysis, and chemical fingerprinting, to authenticate and validate various species/varieties of Wedelia, a reputed medicinal plant that grows naturally and commonly used in Asian countries. The anti-inflammatory bioactivities of Wedelia extracts were then evaluated in a DSS-induced murine colitis model. Different species/varieties of Wedelia exhibited distinguishable morphology and histological structures. Analysis of the ribosomal DNA internal transcribed spacer (ITS) region revealed significant differences among these plants. Chemical profiling of test Wedelia species demonstrated candidate index compounds and distinguishable secondary metabolites, such as caffeic acid derivatives, which may serve as phytochemical markers or index for quality control and identification of specific Wedelia species. In assessing their effect on treating DSS induced-murine colitis, we observed that only the phytoextract from W. chinensis species exhibited significant anti-inflammatory bioactivity on DSS-induced murine colitis among the various Wedelia species commonly found in Taiwan. Our results provide a translational research approach that may serve as a useful reference platform for biotechnological applications of traditional phytomedicines. Our findings indicate that specific Wedelia species warrant further investigation for potential treatment of human inflammatory bowel disease.