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1.
BMC Complement Med Ther ; 24(1): 186, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38734604

RESUMO

BACKGROUND: Cepharanthin® alone or in combination with glucocorticoid (GC) has been used to treat chronic immune thrombocytopenia (ITP) since the 1990s. Cepharanthine (CEP) is one of the main active components of Cepharanthin®. The purpose of this study was to investigate the effects of CEP on GC pharmacodynamics on immune cells and analyse the possible action mechanism of their interactions. METHODS: Peripheral blood mononuclear cells (PBMCs), T lymphocytic leukemia MOLT-4 cells and daunorubicin resistant MOLT-4 cells (MOLT-4/DNR) were used to evaluate the pharmacodynamics and molecular mechanisms. Drug pharmacodynamics was evaluated by WST-8 assay. P-glycoprotein function was examined by rhodamine 123 assay. CD4+CD25+Foxp3+ regulatory T cells and Th1/Th2/Th17 cytokines were detected by flow cytometry. P-glycoprotein expression and GC receptor translocation were examined by Western blot. RESULTS: CEP synergistically increased methylprednisolone (MP) efficacy with the suppressive effect on the cell viability of PBMCs. 0.3 and 1 µM of CEP significantly inhibited P-glycoprotein efflux function of CD4+ cells, CD8+ cells, and lymphocytes (P<0.05). 0.03~3 µM of CEP also inhibited the P-glycoprotein efflux function in MOLT-4/DNR cells in a concentration-dependent manner (P<0.001). However, 0.03~3 µM of CEP did not influence P-glycoprotein expression. 0.03~0.3 µM of CEP significantly increased the GC receptor distribution from the cytoplasm to the nucleus in a concentration-dependent manner in MOLT-4/DNR cells. The combination did not influence the frequency of CD4+, CD4+CD25+ and CD4+CD25+Foxp3+ T cells or the secretion of Th1/Th2/Th17 cytokines from PBMCs. In contrast, CEP alone at 1 µM decreased the percentage of CD4+ T cell significantly (P<0.01). It also inhibited the secretion of IL-6, IL-10, IL-17, TNF-α, and IFN-γ. CONCLUSIONS: CEP synergistically promoted MP pharmacodynamics to decrease the cell viability of the mitogen-activated PBMCs, possibly via inhibiting P-glycoprotein function and potentiating GC receptor translocation. The present study provides new evidence of the therapeutic effect of Cepharanthin® alone or in combination with GC for the management of chronic ITP.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Benzilisoquinolinas , Sinergismo Farmacológico , Leucócitos Mononucleares , Metilprednisolona , Receptores de Glucocorticoides , Humanos , Benzilisoquinolinas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Metilprednisolona/farmacologia , Receptores de Glucocorticoides/metabolismo , Benzodioxóis
2.
Clin Exp Rheumatol ; 41(9): 1777-1783, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36826781

RESUMO

OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease. Methotrexate (MTX) and prednisolone (PSL) are used in combination for severe RA therapy. However, it can increase the risk of osteoporosis and osteonecrosis. Saireito (114) can be used to reduce PSL dose owing to its immunosuppressive effects. However, the effect of combination therapy of PSL+114 on the immune system of RA patients remains unknown. This study compared the effect of PSL alone and PSL+114 on peripheral blood mononuclear cell (PBMC) proliferation, T-cell subsets, and cytokine production in adult RA patients receiving MTX monotherapy. METHODS: We isolated PBMCs from 14 consenting RA patients, and cultured them with PSL (0.0001-1.0 µM) in combination with or without 114 (300 µg/mL) for 96 h in the presence of concanavalin A. We measured the proliferation rates of PBMC, proportions of CD4+, CD8+, and CD4+CD25+Foxp3+T-cells (induced T-regulatory cells), and concentrations of interferon-γ, interleukin (IL)-6, IL-10, IL-17A, and tumour necrosis factor in the culture supernatant. RESULTS: Compared to the blank, the PBMC proliferation rate significantly decreased at a reduced PSL concentration after 114 administration. The 50% inhibition concentration was 0.43 µM PSL for the PSL-only group as compared to 0.29 µM PSL for the PSL+114 co-administration group. The PSL+114 co-administration group had a significantly higher concentration of IL-6 compared to the PSL-only group. CONCLUSIONS: The use of 114 in combination with low-concentration PSL intensified its immunosuppressive effect. However, the concentration of IL-6 was elevated in the co-administration group, suggesting exacerbation of RA activity.


Assuntos
Antirreumáticos , Artrite Reumatoide , Adulto , Humanos , Prednisolona/efeitos adversos , Antirreumáticos/efeitos adversos , Leucócitos Mononucleares , Interleucina-6 , Metotrexato/efeitos adversos
3.
Microbiome ; 10(1): 31, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-35184756

RESUMO

BACKGROUND: Establishing fecal microbiota transplantation (FMT) to prevent multifactorial diarrhea in calves is challenging because of the differences in farm management practices, the lack of optimal donors, and recipient selection. In this study, the underlying factors of successful and unsuccessful FMT treatment cases are elucidated, and the potential markers for predicting successful FMT are identified using fecal metagenomics via 16S rRNA gene sequencing, fecal metabolomics via capillary electrophoresis time-of-flight mass spectrometry, and machine learning approaches. RESULTS: Specifically, 20 FMT treatment cases, in which feces from healthy donors were intrarectally transferred into recipient diarrheal calves, were conducted with a success rate of 70%. Selenomonas was identified as a microorganism genus that showed significant donor-recipient compatibility in successful FMT treatments. A strong positive correlation between the microbiome and metabolome data, which is a prerequisite factor for FMT success, was confirmed by Procrustes analysis in successful FMT (r = 0.7439, P = 0.0001). Additionally, weighted gene correlation network analysis confirmed the positively or negatively correlated pairs of bacterial taxa (family Veillonellaceae) and metabolomic features (i.e., amino acids and short-chain fatty acids) responsible for FMT success. Further analysis aimed at establishing criteria for donor selection identified the genus Sporobacter as a potential biomarker in successful donor selection. Low levels of metabolites, such as glycerol 3-phosphate, dihydroxyacetone phosphate, and isoamylamine, in the donor or recipients prior to FMT, are predicted to facilitate FMT. CONCLUSIONS: Overall, we provide the first substantial evidence of the factors related to FMT success or failure; these findings could improve the design of future microbial therapeutics for treating diarrhea in calves. Video abstract.


Assuntos
Diarreia , Transplante de Microbiota Fecal , Animais , Bovinos , Diarreia/microbiologia , Diarreia/terapia , Transplante de Microbiota Fecal/métodos , Fezes/microbiologia , RNA Ribossômico 16S/genética , Resultado do Tratamento
4.
Fundam Clin Pharmacol ; 35(5): 832-842, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33780033

RESUMO

BACKGROUND: Methotrexate (MTX) is used as anchor drug for patients with early and established rheumatoid arthritis (RA). Vitamin K2 administration was also reported to be associated with decreased disease activity in RA. OBJECTIVES: Immunosuppressive pharmacodynamics of vitamin K2 combined with MTX was investigated. METHODS: Mitogen-activated peripheral blood mononuclear cells (PBMCs) were used to evaluate immunosuppressive pharmacodynamics of drugs in vitro. RESULTS: Vitamin K2 alone dose-dependently suppressed T cell mitogen-activated proliferation of PBMCs of both healthy subjects and RA patients. 446.5 and 2232.5 ng/mL vitamin K2 significantly decreased the IC50 values of MTX on the proliferation of PBMCs of RA patients, with little influences on the pharmacodynamics of MTX in the healthy PBMCs. 4465 ng/mL vitamin K2 potentiated the pharmacodynamics of MTX in both RA patients and healthy PBMCs. The additional effects of vitamin K2 to potentiate the suppressive effects of MTX seemed not to be related to the regulation of CD4+ CD25+ T cells or CD4+ CD25+ Foxp3+ Treg cells. MTX alone at 100 ng/mL significantly decreased the percentage of CD4+ T cells in PBMCs of healthy subjects (p < 0.001) with a slight influence in that of RA patients (not significant) and the combination did not show synergistic inhibitory effect. Vitamin K2 alone tended to suppress the secretion of IL-17, IFN-γ, and TNF-α from the activated PBMCs of RA patients with smaller influences on the cytokine productions from healthy PBMCs. These additional effects of vitamin K2 were also observed in combination with MTX. CONCLUSION: The above information may partially elucidate the potentiation effects of vitamin K2 on the immunosuppressive efficacy of MTX.


Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Metotrexato/farmacologia , Vitamina K 2/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Artrite Reumatoide/metabolismo , Quimioterapia Combinada , Feminino , Voluntários Saudáveis , Humanos , Concentração Inibidora 50 , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Vitamina K 2/administração & dosagem , Vitamina K 2/uso terapêutico , Adulto Jovem
5.
Biol Pharm Bull ; 44(1): 7-17, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390552

RESUMO

Vitamin K2 is suggested to have a suppressive effect on the peripheral blood mononuclear cells (PBMCs) of pediatric atopic dermatitis patients. We examined the molecular targets of vitamin K2 to suppress proliferation and cytokine production in T-cell mitogen-activated PBMCs of atopic dermatitis patients from the viewpoint of mitogen-activated protein kinase signaling molecules. The study population included 16 pediatric vitamin K2 patients and 21 healthy subjects. The effect of vitamin K2 on concanavalin A-activated PBMC proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell counting assays. T-helper (Th)1/Th2/Th17 cytokine profiles in plasma and PBMC-culture supernatants were analyzed by a cytometric beads array assay. Mitogen-activated protein kinase signaling molecules in concanavalin A-activated PBMCs were examined by enzyme-linked immunosorbent assay (ELISA) assays. At 10-100 µM, vitamin K2 significantly suppressed the proliferation of mitogen-activated PBMCs derived from atopic dermatitis patients and healthy subjects (p < 0.05). The interleukin (IL)-10 concentrations in plasma and the PBMC culture supernatants of atopic dermatitis patients were significantly higher than those of healthy subjects (p < 0.05). The IL-2 concentrations in the culture supernatants of atopic dermatitis PBMCs were significantly lower than those of healthy PBMCs (p < 0.05). Vitamin K2 significantly inhibited the IL-17A, IL-10, and tumor necrosis factor α (TNF-α) production (p < 0.05), and increased the IL-2 production (p < 0.01) in the culture supernatant of atopic dermatitis PBMCs. At 10-100 µM, vitamin K2 markedly decreased the of Mek1, extracellular signal-regulated kinases (ERK)1/2 mitogen-activated protein kinase, and SAPK/c-Jun N-terminal kinase (JNK) expression in atopic dermatitis PBMCs (p < 0.05). Vitamin K2 is suggested to attenuate activated T-cell immunity in atopic dermatitis patients through the inhibition of mitogen-activated protein kinase-Mek1-ERK1/2 and SAPK/JNK signaling pathways.


Assuntos
Proliferação de Células/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Dermatite Atópica , Linfócitos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Vitamina K 2/farmacologia , Adolescente , Adulto , Proliferação de Células/fisiologia , Células Cultivadas , Criança , Pré-Escolar , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Linfócitos/metabolismo , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Vitamina K 2/uso terapêutico , Adulto Jovem
6.
Artigo em Inglês | MEDLINE | ID: mdl-33187937

RESUMO

OBJECTIVE: The objective of this study was to investigate the prognostic effects of clinical and histologic findings in patients with mucoepidermoid carcinoma (MEC) of minor salivary glands. STUDY DESIGN: This retrospective clinical review included 63 patients (30 males, mean age 52.8 years) with minor salivary gland MEC treated at our hospital from 1994 to 2019. Overall survival (OS) or disease-free survival was determined using the Kaplan-Meier limit method. Correlations between different factors and survival rates were assessed using chi-square tests. RESULTS: The 10-year OS rate was 91.2%. Low- or intermediate-grade MEC had a good prognosis regardless of the surgical margin, whereas high-grade MEC had a poor 10-year OS rate (64.2%). Ten patients developed recurrence or metastasis after primary surgical resection, of whom 6 were diagnosed with a high-grade tumor. The most frequently affected site was the palate, whereas the mandibular gingiva was the most commonly affected site during recurrence. Of 4 patients who received chemotherapy and/or radiotherapy postsurgery, 2 had local recurrence and/or neck lymph node metastasis and 1 died from MEC. CONCLUSION: Patients with low- or intermediate-grade MEC exhibited satisfactory survival after surgery. In patients with high-grade tumors, it has been suggested that survival rates are poor and do not improve following adjuvant therapy.


Assuntos
Carcinoma Mucoepidermoide , Neoplasias das Glândulas Salivares , Carcinoma Mucoepidermoide/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/cirurgia , Glândulas Salivares Menores
7.
Drug Dev Res ; 82(2): 251-258, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33006164

RESUMO

Sinomenine (SN) is a plant-derived alkaloid isolated from Caulis Sinomenii. It has been approved by the State Food and Drug Administration of China for treating rheumatoid arthritis (RA) nearly 20 years ago. To investigate the anti-RA mechanism of SN, a lot of scholars reported the immunosuppressive effect of SN on T lymphocytes. We continued to evaluate the suppressive function of SN by using human peripheral blood mononuclear cells (PBMCs) isolated from RA patients. As the positive control, 10 ng/ml of methylprednisolone (MP) showed the antiproliferation effect on mitogen-activated PBMCs of RA patients significantly (*p < .05). Meanwhile, MP decreased the frequency of CD4+ CD25+ T cells and suppressed the secretion of inflammatory Th1/Th2/Th17 cytokines such as IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α. However, SN at concentrations of 0.3-30 µM, showed little suppressive effects on the proliferation of PBMCs of RA patients. We did not observe any suppressive effects of SN on percentages of CD4+ T cells and CD4+ CD25+ T cells in the mitogen-activated PBMCs of RA patients. The influence of SN on the percentage of CD4+ CD25+ Foxp3+ T cells was also limited. Finally, even 30 µM of SN did not influence the secretion of Th1/Th2/Th17 cytokine significantly. The present study provided evidence that anti-RA mechanism of SN seems not to be related with the suppressive effects on peripheral T cells.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Citocinas/antagonistas & inibidores , Leucócitos Mononucleares/efeitos dos fármacos , Morfinanos/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , Idoso , Antirreumáticos/farmacologia , Artrite Reumatoide/sangue , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Morfinanos/farmacologia , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento
8.
Cranio ; 39(4): 362-366, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31156068

RESUMO

Background: Synovial chondromatosis is usually detected at a late stage based on free bodies in joint space. The purpose of this study was to identify biomarkers for cell proliferation and chondrogenesis in the primary stage of synovial chondromatosis in the temporomandibular joint (TMJ).Clinical Presentation: A 67-year-old female was referred for right side TMJ pain. Magnetic resonance imaging (MRI) findings suggested an intra-joint space lesion, but no free bodies were observed intraoperatively. Pathological examination led to diagnosis of Milgram stage 1 synovial chondromatosis. Biomarkers related to mesenchymal stem cells (MSCs), cell proliferation, and chondrogenesis were observed in immunohistopathological examination of specimens.Clinical Relevance: The findings suggest that MSCs with chondrogenic potential and growth activity are present at the start of cartilage formation in the synovial membrane. These cells may be the origin of disease. Those findings improve understanding of the etiology and disease progression of synovial chondromatosis in the TMJ.


Assuntos
Condromatose Sinovial , Condromatose , Transtornos da Articulação Temporomandibular , Idoso , Biomarcadores , Condromatose Sinovial/diagnóstico por imagem , Feminino , Humanos , Articulação Temporomandibular , Transtornos da Articulação Temporomandibular/diagnóstico por imagem
9.
Int J Clin Pharmacol Ther ; 59(1): 55-62, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33040843

RESUMO

OBJECTIVE: To investigate the immunosuppressive effect of vitamin K2 against mitogen-activated peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients. MATERIALS AND METHODS: Concanavalin A-stimulated PBMC culture procedure was used to evaluate the pharmacodynamics of vitamin K2 in vitro. Methotrexate was set up as the positive control. The proliferation of PBMCs was detected by MTT assay. Relationship between IC50 values of drugs on PBMC proliferation and patient-related factors including laboratory data was analyzed by nonparametric Spearman correlation test. RESULTS: Vitamin K2 inhibited the proliferation of mitogen-activated PBMCs of RA patients with an IC50 value of 3,288.47 ± 4,910.02 ng/mL (mean ± SD). There was a significant correlation between IC50 values of vitamin K2 and patient-related factors of RA patients (p < 0.05), such as C-reactive protein (CRP), rheumatoid factor, anti-cyclic citrullinated peptide antibody (ACPA), matrix metalloproteinase-3, Pre-DAS-28 (CRP), and ∆DAS-28 (CRP). It would be possible to predict the pharmacodynamics of vitamin K2 in RA patients according to the above factors. Methotrexate inhibited the proliferation of mitogen-activated PBMCs of RA patients with a IC50 value of 22.83 ± 12.47 ng/mL (mean ± SD). IC50 values of methotrexate only showed significant correlation with ACPA (p = 0.0158, r = 0.6905), which suggests that ACPA might be a suitable predictor of the pharmacodynamics of methotrexate. CONCLUSION: The above information suggests that vitamin K2 could provide a benefit for the treatment of RA patients via its immunosuppressive function.


Assuntos
Artrite Reumatoide , Mitógenos , Artrite Reumatoide/tratamento farmacológico , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Leucócitos Mononucleares , Mitógenos/farmacologia , Vitamina K 2
10.
Z Naturforsch C J Biosci ; 76(1-2): 21-25, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33119545

RESUMO

Natural compound tetrandrine was reported to inhibit the proliferation of T cells by inhibiting activation of NF-κB. Chemically, isotetrandrine differs from tetrandrine only in the stereochemistry at the chiral centers. The present study aimed to compare their anti-proliferation effects on human T cells with a focus on NF-κB. The IC50 values of tetrandrine against MOLT-4 cells, MOLT-4/DNR cells, and concanavalin A-activated peripheral blood mononuclear cells of healthy subjects and dialysis patients were 4.43 ± 0.22, 3.62 ± 0.22, 1.91 ± 0.22 and 3.03 ± 0.28 µM, respectively. Whereas, the IC50 values of isotetrandrine against the above immune cells were 2.19 ± 0.27, 2.28 ± 0.33, 1.29 ± 0.14 and 1.55 ± 0.26 µM, respectively. The inhibitory effect of isotetrandrine against the proliferation of T cells was stronger than that of tetrandrine significantly (p < 0.05). Molecular mechanism investigation showed that 10 µM of isotetrandrine largely decreased the expression of p-NF-κB and NF-κB in both MOLT-4 and MOLT-4/DNR T cells (p < 0.05), whereas 10 µM of tetrandrine slightly inhibited the phosphorylation of p-NF-κB with little influence on the expression of NF-κB. Taken together, absolute configurations of tetrandrine and isotetrandrine are suggested to influence on their anti-proliferation effects in human T cells via different regulation of NF-κB.


Assuntos
Benzilisoquinolinas/química , Proliferação de Células , Linfócitos T/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Linhagem Celular Tumoral , Humanos , NF-kappa B/metabolismo , Relação Estrutura-Atividade , Linfócitos T/metabolismo , Linfócitos T/fisiologia
11.
Pharmacol Ther ; 217: 107659, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800789

RESUMO

Inappropriately activated T cells mediate autoimmune diseases and T cell acute lymphoblastic leukemia (T-ALL). Glucocorticoid and chemotherapeutic agents have largely extended lives of these patients. However, serious side effects and drug resistance often limit the prognosis of considerable number of the patients. The efficient treatment of autoimmune diseases or T-ALL with drug resistance remains an important unmet demand clinically. Bisbenzylisoquinoline alkaloids tetrandrine and cepharanthine have been applied for the treatment of certain types of autoimmune diseases and cancers, while studies on their action mechanisms and their further applications combined with glucocorticoids or chemotherapeutic agents remains to be expanded. This review introduced molecular mechanisms of tetrandrine and cepharanthine in T cells, including their therapeutic implications. Both tetrandrine and cepharnthine influence the growth of activated T cells via several kinds of signaling pathways, such as NF-κB, caspase cascades, cell cycle, MAPK, and PI3K/Akt/mTOR. According to recent preclinical and clinical studies, P-glycoprotein inhibitory effect of tetrandrine and cepharnthine could play a significant role on T cell-involved refractory diseases. Therefore, tetrandrine or cepharanthine combined with glucocorticoid or other anti-leukemia drugs would bring a new hope for patients with glucocorticoid-resistant autoimmune disease or refractory T-ALL accompanied with functional P-glycoprotein. In conclusion, bisbenzylisoquinoline alkaloids tetrandrine and cepharanthine can regulate several signaling pathways in abnormally activated T cells with low toxicity. Bisbenzylisoquinoline alkaloids deserve to be paid more attention as a lead compound to develop new drugs for the treatment of T cell-involved diseases in the future.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Benzilisoquinolinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Regulação para Baixo , Quimioterapia Combinada , Glucocorticoides/uso terapêutico , Humanos , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
12.
Oncol Rep ; 44(3): 1293, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32582993

RESUMO

Following the publication of the above paper, an interested reader drew to our attention the fact that the same ß­actin bands had been included in the western blots featured in Figs. 7 and 10. Upon consulting the authors in relation to this matter, they were able to offer a legitimate explanation for this apparent duplication of the bands; essentially, in the western blotting experiments, different antibodies were used in one membrane to present different target proteins by stripping and reprobing the membrane. That the authors had performed this additional step in their protocol was inadvertently omitted from the 'Western blot analyses' subsection of the Materials and methods section. The authors are grateful to the interested reader for drawing this matter to their attention, and apologize for any inconvenience caused to the readership of the Journal. [the original article was published in Oncology Reports 41: 27-42, 2019; DOI: 10.3892/or.2018.6780].

13.
Eur J Pharmacol ; 881: 173232, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32525004

RESUMO

Glucocorticoids are used as anticancer and immunosuppressive agents, whereas glucocorticoid resistance has been observed in a significant fraction of patients due to overexpression of P-glycoprotein encoded by multi-drug resistance-1 gene. Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from traditional herb Fangji. According to our previous report, tetrandrine potentiated glucocorticoid pharmacodynamics partially via inhibiting P-glycoprotein function. In the present study, we investigated whether glucocorticoid receptor translocation was influenced indirectly by tetrandrine via P-glycoprotein inhibition, using human T lymphoblastoid leukemia MOLT-4 cell line with little P-glycoprotein expression and its multidrug resistant sub-line MOLT-4/DNR exhibiting a large amount of P-glycoprotein. Molecular mechanism investigation suggested that overexpressed P-glycoprotein weakened the glucocorticoid receptor translocation in MOLT-4/DNR cells comparing with the parent MOLT-4 cells. Our data also suggested that tetrandrine enhanced nuclear glucocorticoid receptor translocation in MOLT-4/DNR cells indirectly by dual influences on P-glycoprotein, inhibiting the efflux function and downregulating the protein expression. Therefore, tetrandrine potentiated the cytotoxic effect of methylprednisolone against MOLT-4/DNR cells with less effects on MOLT-4 cells. These effects of tetrandrine were suggested to be beneficial for the treatment of glucocorticoid resistant diseases induced by the overexpression of P-glycoprotein.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Benzilisoquinolinas/farmacologia , Daunorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia de Células T/tratamento farmacológico , Receptores de Glucocorticoides/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Transporte Ativo do Núcleo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia de Células T/genética , Leucemia de Células T/metabolismo , Leucemia de Células T/patologia , Transdução de Sinais
14.
Chem Biol Drug Des ; 96(4): 1134-1147, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32305047

RESUMO

The present study was undertaken to evaluate cytotoxic effects of vitamin K1 (phylloquinone), vitamin K2 (menaquinones), and vitamin K3 (menadione) against human T lymphoblastoid leukemia cells, Jurkat T cells, MOLT-4 cells, and P-glycoprotein-expressing multidrug-resistant MOLT-4/DNR cells. Vitamins K2 and K3, but not vitamin K1, reduced viabilities of Jurkat, MOLT-4, and MOLT-4/DNR cells. The influence potency of vitamin K3 was larger than that of vitamin K2 in all of the three cell lines. MOLT-4/DNR cells seemed to be more sensitive toward the effects of vitamins K2 and K3. The cytotoxicity of vitamins K2 and K3 on these leukemia cells seems to be related to apoptosis induction and cell cycle arrest. Vitamin K2 and K3 treatment induced cleavage of PARP obviously. Moreover, vitamins K2 and K3 specifically down-regulated the expressions of cyclin A2 in all of the three cell lines. However, the effects of vitamins K2 and K3 on the cell cycle profiling in Jurkat, MOLT-4, and MOLT-4/DNR cells varied with the cell type. Vitamins K2 and K3 also decreased the viability of mitogen-activated human peripheral blood mononuclear cells. Our observations suggest that vitamins K2 and K3 have bilateral cytotoxic effects on activated human peripheral lymphocytes and the human leukemic T cells.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Leucemia de Células T/patologia , Vitamina K 1/farmacologia , Vitamina K 2/farmacologia , Vitamina K 3/farmacologia , Linhagem Celular Tumoral , Humanos
15.
Pediatr Int ; 61(12): 1188-1195, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31560147

RESUMO

BACKGROUND: Over 20 kinds of steroids, tacrolimus ointments, and cyclosporine capsules are usually recommended for the treatment of atopic dermatitis (AD), depending on the symptoms of patients. However, several side effects sometimes occur with the extensive use of these agents for the treatment of pediatric AD patients. The purpose of this study was to explore whether vitamin K2 could be a new immunosuppressive candidate for pediatric patients with AD. METHODS: The immunosuppressive efficacy of vitamin K2 was evaluated through a cell-culture procedure using mitogen-activated peripheral blood mononuclear cells (PBMCs) obtained from pediatric AD patients. RESULTS: The mean (SD) IC50 value of vitamin K2 for the proliferation of concanavalin A-activated PBMCs was 15.37 (30.05) µmol/L, while the value for tacrolimus was 0.10 (0.28) ng/mL (0.12 (0.35) nmol/L). There was a significant correlation between the IC50 values for vitamin K2 and those for tacrolimus (P = 0.0001, r = 0.8871). However, there was no significant correlation between the IC50 values of vitamin K2 and those of cyclosporine A or methylprednisolone. A significant correlation between the IC50 values of vitamin K2 or tacrolimus and blood eosinophil counts (P = 0.0099, r = 0.7086 and P = 0.0032, r = 0.7722, respectively) was observed. CONCLUSION: Vitamin K2 -inhibited T-cell mitogen stimulated proliferation of PBMCs from pediatric AD patients in a dose-dependent manner. The PBMCs from pediatric AD patients were more sensitive to the immunosuppressive efficacy of vitamin K2 than the PBMCs from healthy subjects. The individual immunosuppressive pharmacological efficacy of vitamin K2 and of tacrolimus could be inferred from the blood eosinophil count of pediatric AD patients.


Assuntos
Dermatite Atópica/tratamento farmacológico , Imunossupressores/administração & dosagem , Vitamina K 2/administração & dosagem , Adulto , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Criança , Pré-Escolar , Ciclosporina/farmacologia , Feminino , Voluntários Saudáveis , Humanos , Imunossupressores/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Metilprednisolona/farmacologia , Tacrolimo/farmacologia , Vitamina K 2/farmacologia , Vitamina K 2/uso terapêutico
16.
Am J Chin Med ; 47(5): 1149-1170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31311297

RESUMO

Three-dimensionally (3D) cultured tumor cells (spheroids) exhibit more resistance to therapeutic agents than the cells cultured in traditional two-dimensional (2D) system (monolayers). We previously demonstrated that arsenic disulfide (As2S2) exerted significant anticancer efficacies in both 2D- and 3D-cultured MCF-7 cells, whereas 3D spheroids were shown to be resistant to the As2S2 treatment. L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, has been regarded to be a potent candidate for combinatorial treatment due to its GSH modulation function. In the present study, we introduced BSO in combination with As2S2 at a low concentration to investigate the possible enhancing anticancer efficacy by the combinatorial treatment on 2D- and 3D-cultured MCF-7 cells. Our results presented for the first time that the combination of As2S2 and BSO exerted potent anticancer synergism in both MCF-7 monolayers and spheroids. The IC50 values of As2S2 in combinatorial treatment were significantly lower than those in treatment of As2S2 alone in both 2D- and 3D-cultured MCF-7 cells (P<0.01, respectively). In addition, augmented induction of apoptosis and enhanced cell cycle arrest along with the regulation of apoptosis- and cell cycle-related proteins, as well as synergistic inhibitions of PI3K/Akt signals, were also observed following co-treatment of As2S2 and BSO. Notably, the combinatorial treatment significantly decreased the cellular GSH levels in both 2D- and 3D-cultured MCF-7 cells in comparison with each agent alone (P<0.05 in each). Our results suggest that the combinatorial treatment with As2S2 and BSO could be a promising novel strategy to reverse arsenic resistance in human breast cancer.


Assuntos
Antineoplásicos/farmacologia , Arsenicais/farmacologia , Neoplasias da Mama/fisiopatologia , Butionina Sulfoximina/farmacologia , Sulfetos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Técnicas de Cultura de Células , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Células MCF-7 , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo
17.
Chem Biol Interact ; 310: 108726, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255635

RESUMO

Tetrandrine (TET) and cepharanthine (CEP) are two bisbenzylisoquinoline alkaloids isolated from the traditional herbs. Recent molecular investigations firmly supported that TET or CEP would be a potential candidate for cancer chemotherapy. Prognosis of patients with glucocorticoid resistant T cell acute lymphoblastic leukemia (T-ALL) remains poor; here we examined the anti-T-ALL effects of TET and CEP and the underlying mechanism by using the glucocorticoid resistant human leukemia Jurkat T cell line in vitro. TET and CEP significantly inhibited cell viabilities and induced apoptosis in dose- and time-dependent manner. Further investigations showed that TET or CEP not only upregulated the expression of initiator caspases such as caspase-8 and 9, but also increased the expression of effector caspases such as caspase-3 and 6. As the important markers of apoptosis, p53 and Bax were both upregulated by the treatment of TET and CEP. However, TET and CEP paradoxically increased the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1, and activated the survival protein NF-κB, leading to high expression of p-NF-κB. Cell cycle arrest at S phase accompanied by increase in the amounts of cyclin A2 and cyclin B1, and decrease in cylcin D1 amount in cells treated with TET or CEP will be another possible mechanism. During the process of apoptosis in Jurkat T cells, treatment with TET or CEP also increased the phosphorylation of JNK and p38. The PI3K/Akt/mTOR signaling pathway modification appears to play significant role in the Jurkat T cell apoptosis induced by TET or CEP. Moreover, TET and CEP seemed to downregulate the expressions of p-PI3K and mTOR in an independent way from Akt, since these two drugs strongly stimulated the p-Akt expression. These results provide fundamental insights into the clinical application of TET or CEP for the treatment of patients with relapsed T-ALL.


Assuntos
Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Benzilisoquinolinas/uso terapêutico , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Células Jurkat , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
18.
Phytother Res ; 33(1): 187-196, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30357956

RESUMO

Sinomenine has been used as an antirheumatic drug in China. Glucocorticoid combined with sinomenine could be an alternative therapeutic approach. In this study, we evaluated the sinomenine potential effect on glucocorticoid pharmacodynamics in vitro using a human peripheral blood mononuclear cell (PBMC) culture system. We also disclosed the possible action mechanism of sinomenine with a focus on P-glycoprotein function and glucocorticoid receptor (GR) translocation into nucleus. The median (range) of methylprednisolone IC50 values against the PBMC proliferation was 3.18 (0.45-6.81) ng/mL, whereas the median (range) IC50 values of methylprednisolone combined with 0.03, 0.3, 3, and 30 µM sinomenine were 1.85 (0.05-5.15), 0.83 (0.10-3.90), 0.56(0.09-1.62), and 0.59(0.05-1.30) ng/mL, respectively. Sinomenine significantly decreased the IC50 values of methylprednisolone and enhanced the immunosuppressive effect of methylprednisolone (p < 0.05). Sinomenine alone regulated the GR translocation in both Jurkat T cells and normal human PBMCs, and the combination of sinomenine and methylprednisolone showed stronger GR-modulatory activity than methylprednisolone alone. Thus, the additive effect of sinomenine to promote the methylprednisolone immunosuppressive efficacy was suggested to be related to nuclear GR-translocation. However, sinomenine did not significantly inhibit the P-glycoprotein function in the activated PBMCs, suggesting that sinomenine's additive effect seemed to be unrelated with the P-glycoprotein inhibition.


Assuntos
Antirreumáticos/uso terapêutico , Leucócitos Mononucleares/efeitos dos fármacos , Morfinanos/química , Extratos Vegetais/uso terapêutico , Receptores de Glucocorticoides/metabolismo , Antirreumáticos/farmacologia , Proliferação de Células/efeitos dos fármacos , Humanos , Extratos Vegetais/farmacologia
19.
Oncol Rep ; 41(1): 27-42, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30320388

RESUMO

In the present study, the antitumor effects of arsenic disulfide (As2S2) on the proliferative, survival and migratory ability of human breast cancer MCF­7 and MDA­MB­231 cells were investigated, and its potential underlying molecular mechanisms with an emphasis on cell cycle arrest, apoptosis induction, autophagy induction and reactive oxygen species (ROS) generation were determined. The results indicated that As2S2 significantly inhibited the viability, survival and migration of breast cancer cells in a dose­dependent manner. In addition, it was identified that As2S2 induced cell cycle arrest primarily at G2/M phase in the two breast cancer cell lines by regulating the expression of associated proteins, including cyclin B1 and cell division cycle protein 2. In addition to cell cycle arrest, As2S2 also triggered the induction of apoptosis in cells by activating the expression of pro­apoptotic proteins, including caspase­7 and ­8, as well as increasing the B­cell lymphoma 2 (Bcl­2)­associated X protein/Bcl­2 ratio, while decreasing the protein expression of anti­apoptotic B­cell lymphoma extra­large. In addition, As2S2 stimulated the accumulation of microtubule­associated protein 1A/1B­light chain 3 (LC3)­II and increased the LC3­II/LC3­I ratio, indicating the occurrence of autophagy. As2S2 treatment also inhibited the protein expression of matrix metalloproteinase­9 (MMP­9), but increased the intracellular accumulation of ROS in the two breast cancer cell lines, which may assist in alleviating metastasis and attenuating the progression of breast cancer. Taken together, the results of the present study suggest that As2S2 inhibits the progression of human breast cancer cells through the regulation of cell cycle arrest, intrinsic and extrinsic apoptosis, autophagy, MMP­9 signaling and ROS generation.


Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Arsenicais/farmacologia , Neoplasias da Mama/metabolismo , Sulfetos/farmacologia , Apoptose , Autofagia , Neoplasias da Mama/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Espécies Reativas de Oxigênio/metabolismo
20.
Clin Neuropharmacol ; 41(5): 164-170, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30130259

RESUMO

OBJECTIVES: The objective of this study was to investigate the influence of treatment with cholinesterase inhibitors (ChEIs) and calcineurin inhibitors (CNIs) on the occurrence of cramps in myasthenia gravis (MG) patients. METHODS: The frequency and duration of cramp and serum electrolytes were evaluated in 81 patients with MG. The patients were classified using Myasthenia Gravis Foundation of America postintervention status scores based on the treatment and the responsiveness to the treatment. Quantitative MG score, MG activities of daily living score, MG composite score, or MG quality of life 15 score was used to assess the health-related quality of life (QOL). RESULTS: Muscle cramps developed in 44 (54.3%) of 81 MG patients. The scores of MG activities of daily living, MG composite, or MG-QOL 15-item questionnaire in patients with cramp were significantly higher than those in patients without cramps (P = 0.002, P = 0.01, or P = 0.0022, respectively). The serum magnesium concentrations were lower in patients treated with CNI (n = 16) than in those not treated with CNI (n = 65) (P = 0.002). The probability of cramps was significantly higher in patients treated with ChEIs (≥180 mg/d) in addition to CNI than in patients who were treated with a low dose of ChEIs (≤60 mg/d) without concomitant CNI treatment (P = 0.017). CONCLUSIONS: Our data suggested that treatment with a high dose of ChEI and CNI accelerated the probability of cramps and reduced the QOL in MG patients.


Assuntos
Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Cãibra Muscular/induzido quimicamente , Miastenia Gravis/tratamento farmacológico , Atividades Cotidianas , Idoso , Cálcio/sangue , Estudos de Coortes , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Cãibra Muscular/sangue , Miastenia Gravis/sangue , Qualidade de Vida , Estudos Retrospectivos , Inquéritos e Questionários
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