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1.
Int Immunopharmacol ; 94: 107229, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33611057

RESUMO

Psoriatic skin inflammation is mainly driven by complex interactions of infiltrating immune cells and activated keratinocytes. Keratinocytes play an active role in initiating and maintenance of psoriatic skin inflammation by secreting chemokines and cytokines. IL-17A produced by T cells potently upregulates the production of chemokine CCL20 in the keratinocytes, which further chemoattracts IL-17A-producing CCR6+ immune cells to the site of inflammation. Indirubin, an active constituent of indigo naturalis, has been reported to possess anti-inflammatory activities, but whether it can suppress the production of chemokines in keratinocytes is largely unknown. To address this question, IL-17A stimulated HaCaT cells were used as cell model to explore the effects of indirubin on the expression and secretion of chemokines. Also, RNA-seq analysis was performed to extensively understand the entire gene expression changes after indirubin treatment and identify the differentially expressed genes further. Indirubin treatment strongly inhibited CCL20 expression and secretion in IL-17A stimulated HaCaT cells. The inhibitory action of indirubin on CCL20 expression was mainly mediated by TAK1 signaling pathway in a mouse psoriasis-like model and cultured HaCaT cells in vitro. Combining with our previous report, indirubin ameliorated psoriasiform dermatitis by breaking CCL20/CCR6 axis-mediated inflammatory loops. Our results provide novel insights into the mechanisms of indirubin in the treatment of psoriasis.

2.
Int Immunopharmacol ; 89(Pt B): 107057, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33242707

RESUMO

Psoriasis is not only a chronic inflammatory skin disease but also a psychosomatic disorder. Depression is one of the most common associated diseases, which aggravates psoriatic skin lesions and affects the life quality of patients. Clinical experiments establish a correlation between psoriasis and depression; however, the mechanisms yet unclear because only a few related studies are available. Therefore, to investigate whether imiquimod-induced psoriasis-like mice showed depressive-like behavior, 5% imiquimod cream was smeared on the back of mice to induce psoriasis-like skin lesions for 8 days. Consequently, the psoriasis area and severity index (PASI) score, epidermal thickness, expression of Ki67 and CD3+ T lymphocyte, the content of IL-12p70, IL-17A, and IL-23 in skin lesions were increased. The psoriasis-like mice presented significant changes in body mass. The sugar water preference rate, the central area distance and area time, and the content of 3,4-dihydroxyphenylaceticacid (DOPAC) and noradrenaline (NE) in the prefrontal cortex, 5-hydroxytryptamine (5-HT), adrenaline (Ad), and DOPAC in the hippocampus, and Ad and γ-aminobutyric acid (GABA) in the hypothalamus of psoriasis-like mice were significantly decreased. The results showed that after the application of imiquimod, depressive-like behaviors appeared in psoriasis-like mice, and the secretion of related neurotransmitters was disordered. Thus, these mice could be used as animal models for studying psoriasis complicated with depression symptoms.

3.
Front Pharmacol ; 11: 584057, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33041827

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) has affected millions of people worldwide. Critically ill COVID-19 patients develop viral septic syndrome, including inflammatory damage, immune dysfunction, and coagulation disorder. In this study, we investigated ShenFuHuang formula (SFH), a traditional Chinese medicine, which has been widely used as complementary therapy for clinical treatment of COVID-19 in Wuhan, to understand its pharmacological properties. Results of systems pharmacology identified 49 active compounds of SFH and their 69 potential targets, including GSK3ß, ESR1, PPARG, PTGS2, AKR1B10, and MAPK14. Network analysis illustrated that the targets of SFH may be involved in viral disease, bacterial infection/mycosis, and metabolic disease. Moreover, signaling pathway analysis showed that Toll-like receptors, MAPK, PPAR, VEGF, NOD-like receptor, and NF-kappa B signaling pathways are highly connected with the potential targets of SFH. We further employed multiple zebrafish models to confirm the pharmacological effects of SFH. Results showed that SFH treatment significantly inhibited the inflammatory damage by reducing the generation of neutrophils in Poly (I:C)-induced viral infection model. Moreover, SFH treatment could improve the phagocytosis of macrophages and enhance the expression of immune genes in an immune deficiency model. Furthermore, SFH treatment exhibited promising anti-thrombosis effect in a thrombus model. This study provided additional evidence of SFH formula for treating COVID-19 patients with septic syndrome using multiple-scale estimation.

4.
J Stroke Cerebrovasc Dis ; 29(10): 105164, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912544

RESUMO

INTRODUCTION: The incidence of lung cancer and acute ischemic stroke remains high in recent years, both of which occur mostly in people over 60 years old. In the present study, we aimed to further clarify the pathogenesis of lung cancer-associated acute ischemic stroke (LCA-AIS) by comparing and analyzing clinical characteristics of stroke patients with or without lung cancer. METHODS: A total of 51 patients with lung cancer were selected as the case group (LCSG), and 78 patients without cancer history were adopted as the control group (SG). The data collected in this study included sex, age, traditional cerebrovascular disease risk factors (TCDRFs), blood test index, imaging findings, etiological typing, and prognosis evaluation. SPSS21.0 software was used for statistical analysis. Normally distributed data were analyzed by t-test, and count data were analyzed by chi-square test or exact probability method. P < 0.05 was considered statistically significant. RESULTS: In the case group, the levels of plasma D-dimer, fibrinogen degradation products (FDPs) and NIHSS, as well as the mRS score and mortality of patients, were higher, while the levels of RBC, Hb and Hcy were lower compared with the control group. Imaging findings showed that multivessel involvement was more common in the case group, and the infarcts were more likely to be multiple and involved in both the anterior and posterior circulations. The TOAST classification of LCSG was dominated by stroke of undetermined etiology (SUE) and stroke of other determined etiology (SOE). Statistical analysis showed that the patients were more likely to suffer from acute ischemic stroke within 1 year after the diagnosis of lung cancer (41 cases, 80.39%). CONCLUSIONS: Hypercoagulability and acute multiple brain infarcts were more common in patients with LCA-AIS, and hypoproteinemia and hyponatremia were more likely to occur in these patients, leading to worse prognosis. Patients were most likely to have a stroke within 1 year after the diagnosis of lung cancer.


Assuntos
Infarto Encefálico/etiologia , Neoplasias Pulmonares/complicações , Tromboembolia/etiologia , Trombofilia/etiologia , Idoso , Biomarcadores/sangue , Infarto Encefálico/diagnóstico , Infarto Encefálico/mortalidade , Estudos de Casos e Controles , Avaliação da Deficiência , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Hiponatremia/diagnóstico , Hiponatremia/etiologia , Hipoproteinemia/diagnóstico , Hipoproteinemia/etiologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Fatores de Risco , Tromboembolia/diagnóstico , Tromboembolia/mortalidade , Trombofilia/diagnóstico , Trombofilia/mortalidade , Fatores de Tempo
5.
Oxid Med Cell Longev ; 2020: 3815185, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32908632

RESUMO

Cardiac dysfunction is a critical manifestation of sepsis-induced multiorgan failure and results in the high mortality of sepsis. Our previous study demonstrated that a traditional Chinese medicine formula, Qiang-Xin 1 (QX1), ameliorates cardiac tissue damage in septic mice; however, the underlying pharmacology mechanism remains to be elucidated. The present study was aimed at clarifying the protective mechanism of the QX1 formula on sepsis-induced cardiac dysfunction. The moderate sepsis model of mice was established by cecal ligation and puncture surgery. Treatment with the QX1 formula improved the 7-day survival outcome, attenuated cardiac dysfunction, and ameliorated the disruption of myocardial structure in septic mice. Subsequent systems pharmacology analysis found that 63 bioactive compounds and the related 79 candidate target proteins were screened from the QX1 formula. The network analysis showed that the QX1 active components quercetin, formononetin, kaempferol, taxifolin, cryptotanshinone, and tanshinone IIA had a good binding activity with screened targets. The integrating pathway analysis indicated the calcium, PI3K/AKT, MAPK, and Toll-like receptor signaling pathways may be involved in the protective effect of the QX1 formula on sepsis-induced cardiac dysfunction. Further, experimental validation showed that the QX1 formula inhibited the activity of calcium/calmodulin-dependent protein kinase II (CaMKII), MAPK (P38, ERK1/2, and JNK), and TLR4/NF-κB signaling pathways but promoted the activation of the PI3K/AKT pathway. A cytokine array found that the QX1 formula attenuated sepsis-induced upregulated levels of serum IFN-γ, IL-1ß, IL-3, IL-6, IL-17, IL-4, IL-10, and TNF-α. Our data suggested that QX1 may represent a novel therapeutic strategy for sepsis by suppressing the activity of calcium, MAPK, and TLR4/NF-κB pathways, but promoting the activation of AKT, thus controlling cytokine storm and regulating immune balance. The present study demonstrated the multicomponent, multitarget, and multipathway characteristics of the QX1 formula and provided a novel understanding of the QX1 formula in the clinical application on cardiac dysfunction-related diseases.

6.
J Leukoc Biol ; 108(1): 267-281, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32421901

RESUMO

Psoriasis is a common, chronic multifactorial inflammatory skin disease with both genetic and environmental components. A number of studies have suggested that psoriasis episodes are often preceded by stressful life events. Nevertheless, the underline mechanisms of stress in psoriasis remain unexplored. To address this question, we established an emotional stress mouse model induced by empty bottle stimulation, and applied imiquimod (IMQ), a ligand of TLR7/8 and effective potent immune activator, on the dorsal skin to induce psoriasis-like lesions. We found that empty bottles induced emotional stress exaggerated and prolonged psoriasiform dermatitis, which appeared as more prominent epidermal hyperplasia in the emotional stress mice compared with the control mice. Higher mRNA expression of Il-1ß, Il-17a, and Il-22, as well as higher secretion of IL-1ß, IL-12p40, IL-17, and IL-22 were observed in the skin lesion of emotional stress mice. The emotional stress condition and IMQ treatment synergistically led to higher expression levels of neurotransmitters and their receptors in the skin, especially substance P (SP), we also found that SP could stimulate DCs to secrete more IL-23p40 in vitro. In addition, NK-1R antagonist partially abrogated enhanced epidermal thickness and the level of neurotransmitters in emotional stress mice. Taken together, these results indicate that stress exacerbates and prolongs psoriasiform dermatitis in mice by up-regulating IL-1ß and IL-23p40, which were related to local DCs stimulated by abnormal SP.


Assuntos
Epiderme/patologia , Imiquimode/efeitos adversos , Subunidade p40 da Interleucina-12/biossíntese , Interleucina-1beta/biossíntese , Psoríase/induzido quimicamente , Estresse Psicológico/complicações , Animais , Ansiedade/etiologia , Ansiedade/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Dermatite/etiologia , Dermatite/patologia , Emoções , Epiderme/efeitos dos fármacos , Hiperplasia , Inflamação/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Neurotransmissores/metabolismo , Nociceptores/metabolismo , Psoríase/complicações , Psoríase/patologia , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Regulação para Cima/efeitos dos fármacos
7.
Nat Immunol ; 21(7): 736-745, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32367036

RESUMO

Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1ß) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1ß and GSDMD processing, but abrogates pore formation, thereby preventing IL-1ß release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases.


Assuntos
Dissulfiram/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas de Ligação a Fosfato/antagonistas & inibidores , Piroptose/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Caspase 1/genética , Caspase 1/metabolismo , Inibidores de Caspase/farmacologia , Caspases/metabolismo , Caspases Iniciadoras/genética , Caspases Iniciadoras/metabolismo , Linhagem Celular Tumoral , Dissulfiram/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Lipossomos , Camundongos , Mutagênese Sítio-Dirigida , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo , Piroptose/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sepse/imunologia , Células Sf9 , Spodoptera
8.
J Tradit Chin Med ; 40(2): 317-323, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32242398

RESUMO

OBJECTIVE: To evaluate the clinical efficacy and safety of Qiguiyin (QGY) formula in patients with severe pneumonia in China compared with a placebo. METHODS: This is a multicenter double-blind, placebo-controlled, randomized clinical trial with two parallel arms. There will be 530 patients enrolled and randomized into either the experimental group (QGY formula) or the control group (placebo). Therapies for patients in the two groups above will be based on the conventional therapy. The primary outcome is 28-day mortality. Secondary outcomes include: (a) duration of hospital stay; (b) duration of time in the intensive care unit (ICU) stays; (c) duration of mechanical ventilation; (d) antibiotic DDD value(which means the doses of antibotics during the treatment period); (e) serum procalcitonin (PCT) level; (f) serum C-reactive protein (CRP) level; (g) Pneumonia severity index (PSI) score; (h) Sequential Organ Failure Assessment (SOFA) score; (i) sputum culture results; (j) blood routine examination results; (k) routine urine test results; (l) stool routine examination results; (m) electrocardiogram results; (n) alanine aminotransferase levels; (o) aspartate amino transferase levels; (p) total bilirubin; (q) creatinine levels; (r) urea nitrogen levels; and (s) adverse events. ETHICS AND DISSEMINATION: The protocol has been approved by the Research Ethics Committee of Beijing Hospital of Traditional Chinese Medicine, Affiliated with Capital Medical University (2018BL- 053-02). This trial aims to provide evidence for QGY formula combined with conventional therapy in treating patients with severe bacterial pneumonia, and to verify the clinical effectiveness and safety of QGY formula in China compared with placebo. Additionally, this trial will reveal the effect of QGY formula on delaying/reversing the characteristics of drug-resistant bacteria.

9.
Cell Biol Int ; 44(8): 1640-1650, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32301547

RESUMO

Carnosol is a natural compound with pharmacological action due to its anti-cancer properties. However, the precise mechanism for its anti-carcinogenic effect remains elusive. In this study, we used lymphoblastoid TK6 cell lines to identify the DNA damage and repair mechanisms of carnosol. Our results showed that carnosol induced DNA double-strand breaks (DSBs). We also found that cells lacking tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme related to topoisomerase 1 (TOP1), and tyrosyl-DNA phosphodiesterase 2 (TDP2), an enzyme related to topoisomerase 2 (TOP2), were supersensitive to carnosol. Carnosol was found to induce the formation of the TOP1-DNA cleavage complex (TOP1cc) and TOP2-DNA cleavage complex (TOP2cc). When comparing the accumulation of γ-H2AX foci and the number of chromosomal aberrations (CAs) with wild-type (WT) cells, the susceptivity of the TDP1-/- and TDP2-/- cells were associated with an increased DNA damage. Our results provided evidence of carnosol inducing DNA lesions in TK6 cells and demonstrated that the damage induced by carnosol was associated with abnormal topoisomerase activity. We conclude that TDP1 and TDP2 play important roles in the anti-cancer effect of carnosol.

10.
Front Pharmacol ; 11: 376, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308620

RESUMO

Intestinal barrier dysfunction is an important clinical problem in various acute and chronic pathological conditions. Ferulic acid (FA) can attenuate the intestinal epithelial barrier dysfunction, however, the underlying mechanism remains unclear. The present study aimed to uncover the protective effect of FA on intestinal epithelial barrier dysfunction in a Caco-2 cell model of lipopolysaccharide (LPS) stimulation and the underlying mechanism. Caco-2 cells were pretreated with FA and then exposed to LPS stimulation. The barrier function of Caco-2 cells was evaluated by measuring trans-epithelial resistance (TER) and 4-kDa fluorescein isothiocyanate (FITC)-dextran (FD4) flux, and analyzing the tight junction protein expression and structure. The results showed that decreased TER and increased FITC-FD4 flux were observed in Caco-2 cells stimulated with LPS, but these effects were attenuated by FA pretreatment. FA pretreatment inhibited LPS-induced decrease in occludin and ZO-1 mRNA and protein expression. LPS stimulation decreased miR-200c-3p expression, whereas this decrease was inhibited by FA pretreatment. Furthermore, overexpression of miR-200c-3p strengthened the protective effects of FA on LPS-induced Caco-2 cell barrier dysfunction by decreasing epithelial permeability, increasing occludin and ZO-1 protein expression, and maintaining of ZO-1 protein distribution, while suppression of miR-200c-3p reversed the protective effects of FA. LPS treatment increased the expression of PTEN protein and decreased expression of phosphorylated PI3K and AKT proteins. However, pretreatment of FA inhibited expression of PTEN protein and promoted activation of PI3K/AKT signaling pathway in the LPS-treated Caco-2 cells, and this regulatory effect of FA on the PTEN/PI3K/AKT signaling pathway was strengthened or weakened by miR-200c-3p overexpression or suppression, respectively. Our findings suggested that in Caco-2 cells, FA promotes activation of PI3K/AKT pathway by miR-200c-3p-mediated suppression of the negative mediator PTEN, which, in turn, maintains TJ function and thus ameliorates LPS-induced intestinal epithelial barrier dysfunction.

11.
Toxicol In Vitro ; 65: 104825, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32169435

RESUMO

Luteolin (3',4',5,7-tetrahydroxyflavone), a naturally occurring flavonoid, has been shown to have anticancer activity in many types of cancer cell lines. The anticancer capacity of luteolin may be related to its ability to induce DNA double-strand breaks (DSBs). Here, we used DT40 cells to determine whether nonhomologous end joining (NHEJ) and homologous recombination (HR) are involved in the repair mechanism of luteolin-induced DNA damage. Cells defective in Ku70 (an enzyme associated with NHEJ) or Rad54 (an enzyme essential for HR) were hypersensitive and presented more apoptosis in response to luteolin. Moreover, the sensitivity and apoptosis of Ku70-/- and Rad54-/- cells were associated with increased DNA damage when the numbers of γ-H2AX foci and chromosomal aberrations (CAs) were compared with those from WT cells. Additionally, after treatment with luteolin, Ku70-/- cells presented more Top2 covalent cleavage complexes (Top2cc). These results indicated that luteolin induced DSBs in DT40 cells and demonstrated that both NHEJ and HR participated in the repair of luteolin-induced DSBs, which might be related to the inhibition of topoisomerases. These results imply that simultaneous inhibition of NHEJ and HR with luteolin treatment would provide a powerful protocol in cancer chemotherapy.

12.
Cancer Immunol Res ; 8(5): 660-671, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32161110

RESUMO

We assessed the contribution of IL1 signaling molecules to malignant tumor growth using IL1ß-/-, IL1α-/-, and IL1R1-/- mice. Tumors grew progressively in IL1R-/- and IL1α-/- mice but were often absent in IL1ß-/- mice. This was observed whether tumors were implanted intradermally or injected intravenously and was true across multiple distinct tumor lineages. Antibodies to IL1ß prevented tumor growth in wild-type (WT) mice but not in IL1R1-/- or IL1α-/- mice. Antibodies to IL1α promoted tumor growth in IL1ß-/- mice and reversed the tumor-suppressive effect of anti-IL1ß in WT mice. Depletion of CD8+ T cells and blockade of lymphocyte mobilization abrogated the IL1ß-/- tumor suppressive effect, as did crossing IL1ß-/- mice to SCID or Rag1-/- mice. Finally, blockade of IL1ß synergized with blockade of PD-1 to inhibit tumor growth in WT mice. These results suggest that IL1ß promotes tumor growth, whereas IL1α inhibits tumor growth by enhancing T-cell-mediated antitumor immunity.

13.
J Pain Res ; 13: 75-86, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021397

RESUMO

Objective: Acupuncture has a therapeutic effect similar to that of prophylactic drugs and can be considered a treatment option for migraineurs. However, the mechanism of acupuncture treatment's effect on migraine is uncertain. An approach based on anti-inflammatory effects is an important treatment strategy for migraine because non-steroidal anti-inflammatory drugs (NSAIDs) are usually used during migraine attacks. Meningeal inflammation is thought to be responsible for the activation of the trigeminovascular system. Our previous study found that electroacupuncture (EA) decreased neurogenic inflammation mediator expression in the trigeminal ganglion (TG) and alleviated hyperalgesia. The present study examined whether EA would inhibit hyperalgesia by alleviating neurogenic inflammatory factors. Methods: A rat model of migraine was established using dural electrical stimulation (DES). Five groups were analyzed in this study. The Model group received DES three times to mimic migraine attacks, a Control group had sham DES, and three groups received electroacupuncture after DES: a Non-Acu group at a non-acupuncture point, a GB20 group at GB20, and a GB20/34 group at GB20 and GB34 acupuncture points. We evaluated mechanical hyperalgesia using an electronic von Frey esthesiometer in the awake state. After sacrifice, the dura mater was analyzed using immunofluorescence. Serum calcitonin gene-related peptide, cyclooxygenase-2, brain-derived neurotrophic factor, IL-1ß, IL-6, and TNF levels were determined using enzyme-linked immunosorbent assays to evaluate the anti-inflammatory effect of acupuncture. Results: After repeated DES, we observed facial and hind paw mechanical hyperalgesia, which was inhibited by electroacupuncture. Electrical stimulation increased the number of mast cells and macrophages and serum levels of inflammatory factors. GB20 and GB20/34 electroacupuncture significantly decreased the number of mast cells and macrophages and serum levels of inflammatory factors. Moreover, electroacupuncture at GB20/34 was superior to that at GB20 alone in inhibiting hyperalgesia and alleviating inflammatory factors. Conclusion: Electroacupuncture inhibits DES-induced hyperalgesia by alleviating inflammatory factors. Inhibition of dural mast cells, macrophages, and serum inflammatory factors may be one of the mechanisms involved in acupuncture treatment's effect on migraine.

14.
Trials ; 20(1): 674, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801593

RESUMO

BACKGROUND: Psoriasis is a chronic, immune-mediated disorder with chronic plaque psoriasis being the primary manifestation during the remission stage. Patients often have a slow course and long history of the disease. The refractory type of psoriasis is a stubborn rash that does not subside easily. We designed this randomized controlled trial to compare the effectiveness and relapse rates of plaque psoriasis in patients treated with either acupuncture, moxibustion or calcipotriol ointment. The ultimate aim of the study is to select an effective traditional Chinese medicine therapy for patients with plaque psoriasis. METHODS: The study will be a multicenter, prospective, randomized controlled trial that compares the effectiveness of fire needle therapy, moxibustion and calcipotriol ointment. In total, 160 patients with plaque psoriasis who meet the inclusion criteria will be recruited from three hospitals in Beijing and then randomly assigned to receive either fire needle therapy (group A1), moxibustion (group A2) or calcipotriol ointment (group B). All participants will receive an 8-week treatment and will then be followed up for another 24 weeks, with time points at weeks 12 and 24 after treatment completion. The primary outcomes to be measured are relapse rates and psoriasis area and severity index score of the target lesions. In addition, the target lesion onset time, dermatology life quality index, traditional Chinese medicine syndrome score, and the relapse interval of the target lesion will be measured. Adverse events will be recorded for safety assessment. DISCUSSION: The aim of this study is to determine whether fire needle therapy or moxibustion could improve the clinical effectiveness for psoriasis lesions and reduce the relapse rate. Once completed, it will provide information regarding therapeutic evaluation on fire needle therapy or moxibustion for plaque psoriasis, which will assist clinicians in selecting the most effective treatment options for patients. TRIAL REGISTRATION: International Clinical Trials Registry Platform (ICTRP), ChiCTR1800019588. Registered on 19 November 2018.


Assuntos
Terapia por Acupuntura/métodos , Moxibustão/métodos , Psoríase/terapia , Adolescente , Adulto , Idoso , Calcitriol/análogos & derivados , Calcitriol/uso terapêutico , Doença Crônica , Humanos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Adulto Jovem
15.
Mol Med Rep ; 20(4): 3625-3632, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485668

RESUMO

The aim of this study was to explore the synergistic effect of signal transducer and activator of transcription 3 (STAT3)­targeted small interfering (si)RNA and AZD0530 against glioblastoma in vitro and in vivo. Glioblastoma cell lines U87 and U251 were divided into four groups and treated with control, LV­STAT3 siRNA, AZD0530, and combined LV­STAT3 siRNA with AZD0530, respectively. The proliferation and apoptotic capacity of glioblastoma cells was assessed by Cell Counting Kit­8 and double staining flow cytometry assays, respectively. Additionally, the potential effect of LV­STAT3 siRNA and AZD0530 on glioblastoma was evaluated in vivo. Images were captured of the tumor formation in mice every week. Following three weeks of treatment, NMR scan and immunohistochemistry were performed. The treatment of combined LV­STAT3 siRNA and AZD0530 was more effective in inhibiting proliferation and inducing apoptosisof glioblastoma cells in comparison with the treatment of either LV­STAT3 siRNA or AZD0530 alone. Although LV­STAT3 siRNA or AZD0530 treatment alone suppressed tumor growth in mice, the combined treatment had a more significant effect than the treatment of LV­STAT3 siRNA or AZD0530 alone. According to the results of both in vitro and in vivo assays, a combined therapy of LV­STAT3 siRNA with AZD0530 could enhance therapeutic effects on glioblastoma, supporting the idea that the combination of LV­STAT3 siRNA and AZD0530 could serve as a novel and effective strategy to combat glioblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Benzodioxóis/uso terapêutico , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Quinazolinas/uso terapêutico , Terapêutica com RNAi , Fator de Transcrição STAT3/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada/métodos , Glioblastoma/genética , Glioblastoma/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/métodos
16.
Artigo em Inglês | MEDLINE | ID: mdl-31467575

RESUMO

Psoriasis is a common autoimmune disease. Acupuncture-related techniques have been widely used to treat psoriasis since its ability to engage neuronal function, the immune system, and other systems is well documented. This study aimed to investigate and compare the effects of three common acupuncture-related techniques in psoriasis-like skin inflammatory responses and explore the possible involved mechanisms. Imiquimod (IMQ)-induced psoriasis-like mice were treated with acupuncture needling, electroacupuncture, or fire acupuncture. Methotrexate (MTX) was applied as a positive control. Scoring by the psoriasis area and severity index (PASI) evaluated skin lesion changes. Keratinocyte proliferation and inflammatory cell infiltration were investigated using pathological staining. The secretion levels of inflammatory cytokines were detected by enzyme-linked immunosorbent assay. The expression levels of neuropeptides were assessed by Western immunoblotting. We found that acupuncture needling, electroacupuncture, and fire acupuncture all ameliorated skin lesions, reduced epidermal thickness, inhibited keratinocyte proliferation, and reduced CD3+ T cell infiltration. The aforementioned acupuncture techniques also decreased inflammatory cytokine secretion, including IL-1ß, IL-17A, and IL-23p40. Among them, electroacupuncture showed the best curative effects. Additionally, electroacupuncture downregulated the expression levels of Neurokinin A (NKA), which was positively associated with decreased inflammatory cytokine levels in local lesions. In conclusion, acupuncture needling, electroacupuncture, and fire acupuncture alleviated IMQ-induced psoriasis-like lesions. By contrast, electroacupuncture was more beneficial in reducing the inflammatory response, which might be related to locally dampened neuropeptide levels. Observations support the therapeutic effect of acupuncture for psoriasis and indicate a neuromodulatory mechanism in treating psoriasis by electroacupuncture.

17.
Mol Med Rep ; 19(4): 3217-3229, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816506

RESUMO

Our previous studies suggested that paeonol, the active constituent of the traditional Chinese medicine Cortex Moutan, may be an effective treatment for inflammatory disorders. In the present study, the therapeutic potential of paeonol on atopic dermatitis (AD) was investigated using animal and cell experiments. AD­like lesions were induced by repeated application of 1­chloro­2,4­dinitrobenzene (DNCB) to the shaved dorsal skin of BALB/c mice, and P815 cells were used for in vitro assays. The skin lesions, serum and spleens of the mice were analyzed using lesion severity scoring, histological analysis, flow cytometry, reverse transcription­quantitative polymerase chain reaction, western blotting and ELISA, in order to investigate the anti­AD effects of paeonol. In addition, western blotting and ELISA were conducted for in vitro analysis of P815 cells. The results demonstrated that oral administration of paeonol inhibited the development of DNCB­induced AD­like lesions in the BALB/c mice by reducing severity of the lesions, epidermal thickness and mast cell infiltration; this was accompanied by reduced levels of immunoglobulin E and inflammatory cytokines [interleukin (IL)­4, histamine, IL­13, IL­31 and thymic stromal lymphopoietin], along with regulation of the T helper (Th) cell subset (Th1/Th2) ratio. Application of paeonol also reduced the protein expression levels of phosphorylated (p)­p38 and p­extracellular signal­regulated kinase (ERK) in skin lesions. In vitro, paeonol reduced the expression levels of tumor necrosis factor­α and histamine in P815 cells, and inhibited p38/ERK/mitogen­activated protein kinase signaling. The present findings indicated that paeonol may relieve dermatitis by acting on cluster of differentiation 4+ T and mast cells; therefore, paeonol may represent a potential therapeutic strategy for the treatment of allergic inflammatory conditions via immunoregulation.


Assuntos
Acetofenonas/farmacologia , Dermatite Atópica/etiologia , Dermatite Atópica/metabolismo , Dinitroclorobenzeno/efeitos adversos , Mastócitos/imunologia , Mastócitos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Biomarcadores , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Mediadores da Inflamação/metabolismo , Camundongos , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
18.
Onco Targets Ther ; 12: 1857-1865, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881038

RESUMO

Glioblastoma multiforme (GBM) is the most common and aggressive adult primary central nervous system tumor. Unfortunately, GBM is resistant to the classic chemotherapy drug, temozolomide (TMZ). As well as its classic DNA-targeting effects, the off-target effects of TMZ can have pro-survival or pro-death roles and regulate GBM chemoradiation sensitivity. Endoplasmic reticulum (ER) stress is one of the most common off-target effects. ER stress and its downstream induction of autophagy, apoptosis, and other events have important roles in regulating TMZ sensitivity. Autophagy is an evolutionarily conserved cellular homeostasis mechanism that is closely associated with ER stress-induced apoptosis. Under ER stress, autophagy cannot only remove misfolded/unfolded proteins and damaged organelles and degrade and inhibit apoptosis-related caspase activation to reduce cell damage, but may also promote apoptosis dependent on ER stress intensity. Although some protein interactions between autophagy and apoptosis and common upstream signaling pathways have been found, the underlying regulatory mechanisms are still not fully understood. This review summarizes the possible mechanisms underlying the current known off-target roles of ER stress and downstream autophagy in the regulation of cell fate and evaluates their role in TMZ treatment and their potential as therapeutic targets.

19.
Contemp Nurse ; 55(4-5): 288-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30369293

RESUMO

Background: Few studies have examined whether nursing undergraduates can cope with a problem-based learning curriculum and its associated factors.Objectives: We studied nursing undergraduates' evaluations and attitudes related to the problem-based learning teaching method and their associated factors in the Chinese context, and evaluated their self-efficacy for coping with the problem-based learning curricula.Methods: A purposely designed 20-item questionnaire was used to quantify how nursing undergraduates evaluated the problem-based learning mode and their associated factors. Coping self-efficacy was measured with a modified Chinese version of the scale.Results: The total coping self-efficacy score of nursing undergraduates was 53.32 ± 5.238 (M ± SD).Conclusions: The coping self-efficacy of nursing undergraduates was moderate, making them better qualified to cope with a problem-based learning curriculum. To increase nursing undergraduates' coping self-efficacy, we should take measures to decrease nursing undergraduates' stress regarding problem-based learning curricula and give them more opportunities to obtain abundant periodicals through the internet.


Assuntos
Adaptação Psicológica , Currículo , Aprendizagem Baseada em Problemas , Autoeficácia , Estudantes de Enfermagem/psicologia , Bacharelado em Enfermagem/métodos , Humanos
20.
Int J Hyperthermia ; 35(1): 112-121, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30010455

RESUMO

PURPOSE: Intestinal epithelial barrier dysfunction is crucial in the pathogenesis of intestinal and systemic diseases. Ferulic acid (FA) possesses promising antioxidant activities. In a previous study, we demonstrated potentially protective effects of FA against heat stress-induced intestinal epithelial barrier dysfunction in IEC-6 cells. However, the underlying mechanisms are unclear. The present study aimed to elucidate whether FA protects IEC-6 cells from heat stress-induced intestinal epithelial barrier dysfunction via antioxidative mechanisms. MATERIALS AND METHODS: IEC-6 cells were pretreated with FA prior to hyperthermia exposure at 42 °C for 6 h, and the levels of intracellular reactive oxygen species (ROS), malondialdehyde (MDA), nitrogen oxide (NO), and superoxide dismutase (SOD) activity were analyzed. The intestinal epithelial barrier function was determined by transepithelial electrical resistance (TER) values and 4-kDa fluorescein isothiocyanate-dextran (FD4) flux in IEC-6 cell monolayers. Expression of related proteins was detected by Western blotting. RESULTS: FA suppressed heat stress-induced intestinal oxidative stress damage by reducing ROS, MDA and NO production, while enhancing SOD activity. Furthermore, FA treatment strengthened intestinal barrier function via increasing the phosphorylation levels of Akt, nuclear factor-erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) protein expression, which was reversed by zinc protoporphyrin (an HO-1 inhibitor). Additionally, LY294002, a specific PI3K/Akt inhibitor, significantly suppressed FA-induced Nrf2 nuclear translocation and HO-1 protein expression and inhibited FA-induced occludin and ZO-1 protein expression. CONCLUSIONS: FA protected against heat stress-induced intestinal epithelial barrier dysfunction via activating the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in IEC-6 cells.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Ácidos Cumáricos/uso terapêutico , Transtornos de Estresse por Calor/tratamento farmacológico , Intestinos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Cumáricos/farmacologia , Transtornos de Estresse por Calor/patologia , Humanos , Ratos , Transdução de Sinais
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