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1.
Chin Med ; 16(1): 121, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34809653

RESUMO

BACKGROUND: Compound kushen injection (CKI), a Chinese patent drug, is widely used in the treatment of various cancers, especially neoplasms of the digestive system. However, the underlying mechanism of CKI in pancreatic cancer (PC) treatment has not been totally elucidated. METHODS: Here, to overcome the limitation of conventional network pharmacology methods with a weak combination with clinical information, this study proposes a network pharmacology approach of integrated bioinformatics that applies a weighted gene co-expression network analysis (WGCNA) to conventional network pharmacology, and then integrates molecular docking technology and biological experiments to verify the results of this network pharmacology analysis. RESULTS: The WGCNA analysis revealed 2 gene modules closely associated with classification, staging and survival status of PC. Further CytoHubba analysis revealed 10 hub genes (NCAPG, BUB1, CDK1, TPX2, DLGAP5, INAVA, MST1R, TMPRSS4, TMEM92 and SFN) associated with the development of PC, and survival analysis found 5 genes (TSPOAP1, ADGRG6, GPR87, FAM111B and MMP28) associated with the prognosis and survival of PC. By integrating these results into the conventional network pharmacology study of CKI treating PC, we found that the mechanism of CKI for PC treatment was related to cell cycle, JAK-STAT, ErbB, PI3K-Akt and mTOR signalling pathways. Finally, we found that CDK1, JAK1, EGFR, MAPK1 and MAPK3 served as core genes regulated by CKI in PC treatment, and were further verified by molecular docking, cell proliferation assay, RT-qPCR and western blot analysis. CONCLUSIONS: Overall, this study suggests that the optimized network pharmacology approach is suitable to explore the molecular mechanism of CKI in the treatment of PC, which provides a reference for further investigating biomarkers for diagnosis and prognosis of PC and even the clinical rational application of CKI.

2.
Mol Plant ; 14(11): 1846-1863, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34271176

RESUMO

Natural alleles that control multiple disease resistance (MDR) are valuable for crop breeding. However, only one MDR gene has been cloned in maize, and the molecular mechanisms of MDR remain unclear in maize. In this study, through map-based cloning we cloned a teosinte-derived allele of a resistance gene, Mexicana lesion mimic 1 (ZmMM1), which causes a lesion mimic phenotype and confers resistance to northern leaf blight (NLB), gray leaf spot (GLS), and southern corn rust (SCR) in maize. Strong MDR conferred by the teosinte allele is linked with polymorphisms in the 3' untranslated region of ZmMM1 that cause increased accumulation of ZmMM1 protein. ZmMM1 acts as a transcription repressor and negatively regulates the transcription of specific target genes, including ZmMM1-target gene 3 (ZmMT3), which functions as a negative regulator of plant immunity and associated cell death. The successful isolation of the ZmMM1 resistance gene will help not only in developing broad-spectrum and durable disease resistance but also in understanding the molecular mechanisms underlying MDR.

3.
J Cell Mol Med ; 25(16): 7948-7960, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34155778

RESUMO

Smoking and Candida albicans (C. albicans) infection are risk factors for many oral diseases. Several studies have reported a close relationship between smoking and the occurrence of C. albicans infection. However, the exact underlying mechanism of this relationship remains unclear. We established a rat infection model and a C. albicans-Leuk1 epithelial cell co-culture model with and without smoke exposure to investigate the mechanism by which smoking contributes to C. albicans infection. Oral mucosa samples from healthy individuals and patients with oral leucoplakia were also analysed according to their smoking status. Our results indicated that smoking induced oxidative stress and redox dysfunction in the oral mucosa. Smoking-induced Nrf2 negatively regulated the NLRP3 inflammasome, impaired the oral mucosal defence response and increased the oral mucosa susceptibility to C. albicans. The results suggest that the Nrf2 pathway could be involved in the pathogenesis of oral diseases by mediating an antioxidative response to cigarette smoke exposure and suppressing host immunity against C. albicans.

4.
Zhongguo Zhong Yao Za Zhi ; 46(2): 412-419, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33645130

RESUMO

In this paper, Asarum polysaccharides(AP) were extracted, and its composition was analyzed to study the activity against H1 N1 influenza virus in vitro and its intervention effect on mice with kidney Yang deficiency syndrome. AP was prepared by the strategy of water extraction and alcohol precipitation, the content was determined, and its monosaccharide composition was analyzed. The cell Real-time monitoring system and Reed-Muench model were adopted to evaluate the antiviral activity of AP in vitro. And the mouse model of kidney Yang deficiency syndrome was established in vivo to compare the efficacy of Mahuang Xixin Fuzi Decoction(MXF) and AP. MXF group and AP group were treated with clinical equivalent doses of 1.8 g·kg~(-1)·d~(-1) and 0.077 g·kg~(-1)·d~(-1) respectively, once a day for 6 consecutive days. Real-time PCR was used to detect the relative expression of M gene of H1 N1 influenza virus and cytokines in lung tissue. The content of AP in Asarum was 25.22%, and the protein content was 0.8%. And the monosaccharide composition was identified as L-rhamnose, D-arabinose, D-xylose, D-glucose, D-galactose and D-mannose. TI values of Tamiflu, MXF and AP were 30.00, 8.06 and 10.33, respectively. Three different doses of AP could significantly reduce the concentration of virus in supernatant. Compared with the model mice, lung indexes of MXF group and AP group decreased significantly(P<0.05), and the relative expression of M gene decreased significantly(P<0.05). The relative expressions of IL-10 and IFN-γ were up-regulated to varying degrees, while the relative gene expressions of IL-1ß, IL-6 and MCP-1 were down-regulated to different degrees. In addition, AP could significantly enhance the expression of TNF-α(P<0.01). AP had a good anti-influenza virus activity in vitro, and could protect mice with kidney Yang deficiency syndrome by reducing the viral load in lung tissue, decreasing inflammation damage in lung tissue, and regulating the expression of inflammatory cytokines. Compared with the prescription of MXF, AP had a better antiviral activity.


Assuntos
Asarum , Medicamentos de Ervas Chinesas , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Animais , Antivirais/uso terapêutico , Citocinas/genética , Influenza Humana/tratamento farmacológico , Influenza Humana/genética , Pulmão , Camundongos , Polissacarídeos
5.
J Chromatogr A ; 1637: 461796, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33387913

RESUMO

The effect of solvents on the enantioselectivities of four structurally similar chiral solutes with a cellulose derivative-based chiral stationary phase, Chiralpak IB, were studied using acetone (AC), 2-propanol (IPA), and tert-butanol (TBA) separately as polar modifiers. The enantioselectivities α of benzoin and methyl mandelate decrease with an increase in modifier concentration CM, whereas the enantioselectivity of pantolactone increased with increasing AC concentration. These results were attributed to the heterogeneous adsorption mechanisms of enantiomers. To interpret the dependence of enantioselectivity on modifier content, an enantioselectivity model based on a two-site adsorption model was proposed. The dependence of α on CM was inferred to be mainly due to the distinct modulating effects of modifier concentration on the two adsorption sites: the nonselective type-I site and enantioselective type-II site. The model fitted the benzoin data satisfactorily over a wide TBA concentration range. The retention factors as a function of TBA concentration were successfully deconvoluted for each site. With the use of the proposed model, it was inferred that the chiral recognitions of benzoin and methyl mandelate were mainly achieved by the presence of an aromatic group adjacent to the hydroxyl group. When using IPA and TBA separately as modifiers, the presence of an aromatic group adjacent to the ketone group mainly contributed to the nonselective π interactions and enantioselective steric interactions, respectively. These results, along with those of the modifier adsorption isotherms, determined using the perturbation method, as well as the retention behaviors of various achiral solutes, indicate that the molecular recognition mechanism of IB sorbent is highly sensitive to the adsorbate's molecular geometry. The molecular environment of the sorbent can be controlled using different modifiers, leading to distinct adsorption and retention mechanisms.


Assuntos
Celulose/química , Solventes/química , Adsorção , Estereoisomerismo
6.
Ann Hematol ; 100(3): 799-808, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33416901

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been regarded as a potential strategy for myeloid sarcoma (MS). The previous reports focused mainly on matched sibling donor (MSD) or matched unrelated donor (MUD) transplantation. There are no reports on haploidentical HSCT (haplo-HSCT) in MS. We retrospectively reviewed 14 MS patients who underwent haplo-HSCT. All patients achieved complete donor engraftment. The median time for neutrophil engraftment and platelet engraftment were 10 (12-21) days and 18 (8-31) days. The 100-day cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) and 3-year cumulative incidence of chronic GVHD were 37.7% (95%CI, 23.2-52.1%) and 35.7% (95%CI, 22.2-49.2%). Cytomegalovirus (CMV) reactivation was documented in 86% patients, and only one patient developed CMV pneumonia. Treatment-related mortality occurred in one (7%) patient. The 1- and 3-year cumulative incidence of relapse was 21.4% (95%CI, 11.8-31.1%) and 35.7% (95%CI, 22.4-49.0%). The probability of overall survival at 1 and 3 years was 71.4% (95%CI, 51.3-99.5%) and 64.3% (95%CI, 43.5-95.0%), respectively. The probability of disease-free survival at 1 and 3 years was 71.4% (95%CI, 51.3-99.5%) and 57.1% (95%CI, 36.3-89.9%), respectively. In conclusion, haplo-HSCT is a feasible method for patients with MS who have no MSD or MUD.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Sarcoma Mieloide/terapia , Transplante Haploidêntico , Adolescente , Adulto , Quimioprevenção , Criança , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Masculino , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/epidemiologia , Sarcoma Mieloide/mortalidade , Irmãos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Haploidêntico/efeitos adversos , Transplante Haploidêntico/estatística & dados numéricos , Resultado do Tratamento , Adulto Jovem
7.
J Orthop Translat ; 23: 152-158, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32913707

RESUMO

Aim: Osteoporotic vertebral compressive fractures (VCFs) â€‹are known to be commonly missed in X-rays indicated for pulmonary or heart diseases. In this study, we investigated the underreporting status of VCF in back pain clinic patients when the spine was the focus of interest. Materials and methods: This is a retrospective analysis of 105 female cases (mean: 72 years, range: 55-93 years) from a tertiary hospital in China (facility A, FA). The patients with back and/or leg pain were referred for a spine X-ray. The images were retrieved and transferred to a central reading facility (facility B, FB), where images were double-read by two readers experienced in evaluating osteoporotic vertebral compressive deformity (VCD)/VCF. A qualitative VCD with <20%, 20-25%, 25-40%, and >40% vertebral body height loss was recorded as minimal, mild, moderate, and severe grades, respectively. A â€‹VCD coexisted with endplate/cortex fracture (ECF) was VCF. FB readings were considered as the reference. Results: There were 34 true negative cases where FA and FB had a consensus. In 7 cases with minimal VCD, 3 cases with ECF, and 7 cases with minimal or mild VCFs, the FA readings were false negative. No standalone singular moderate or severe VCD/VCF in a patient was missed in FA's reports. In 25 FA reading positive cases with multiple VCFs, one VCF was missed in 8 cases, more than one VCF was missed in 15 cases, and one additional ECF was missed in 2 cases. In 14 cases, FA and FB had VCF number agreement, with the term 'vertebral fracture' was used appropriately in FA reports. In 15 cases, FA and FB had agreement in VCF number; however, the appropriate term 'vertebral fracture' was not used in FA reports; instead the terms of 'compressive change' or 'wedging change' were used. In most VCFs, severity grading was not given in FA. In 13 VCFs where grading was reported, all were marked as 'mild', including seven mild VCFs, five moderate VCFs, and even one severe VCF. Conclusion: Among the patients with VCD/VCF, the false negative rate among was 23.9% (17/71), but the missed cases were all minimal or mild grades. One or more VCFs were missed in 32.4% (23/71) of the cases with multiple VCFs. Appropriate severity grading was not reported for most cases. The translational potential of this article: The underreporting rate of osteoporotic vertebral compressive fracture in back pain clinic patients in a typical tertiary hospital setting in China compared favorably with literature reports. However, there is a general lack of awareness of vertebral endplate/cortex fracture sign and vertebral fracture severity grading, while minimal and mild VCD with endplate/cortex fracture may have clinical significance. Moreover, after one VCF is spotted in a patient, it is highly advisable to carefully check the whole spine so that multiple VCFs will not be missed.

8.
Arch Osteoporos ; 15(1): 41, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144508

RESUMO

PURPOSE: Opportunities exist to detect osteoporotic vertebral deformities (VDs) on frontal radiograph (FR) indicated for lung or abdominal diseases, while literature have been mostly based on lateral radiograph (LR). This study analyzed the detectability of moderate and severe grades VD on FR. METHODS: There were 105 female cases (mean 72 years, range 55~93 year), who were referred for digital spine FR and LR with back and/or leg pain. The LR and FR were read, osteoporotic VDs with < 20%, 20-25%, 25-40%, and > 40% vertebral body height loss were recorded as minimal, mild, moderate, and severe grades, respectively. After a 10-month interval, only FRs were read again, and each vertebra was classified as (1) no notable VD, (2) with notable VD, and (3) ambiguous. The first reading was the reference, while the second reading was allowed to miss minimal/mild VCD and endplate/cortex fracture. RESULTS: Counting by subjects, for 98 cases, the two reading sessions had agreement, including 43 "true negative" cases and 55 true positive cases. There were two false positive cases, and five ambiguous cases. In total, 1286 vertebra were assessed, FR reading had 1126 vertebrae "true negative," 130 vertebrae true positive, one vertebra false negative, 3 vertebrae false positive, and 26 ambiguous vertebrae (65.4% being true negative and 34.6% being true positive). Most of the disagreements were associated with kyphosis or poor X-ray projection. Nineteen illustrative cases are presented graphically. CONCLUSION: Moderate and severe grades of VD are identifiable on FR as long as the involved vertebrae are clearly filmed.


Assuntos
Cifose/diagnóstico por imagem , Fraturas por Osteoporose/diagnóstico por imagem , Radiografia/métodos , Fraturas da Coluna Vertebral/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Ilustração Médica , Pessoa de Meia-Idade , Coluna Vertebral/diagnóstico por imagem
9.
J Orthop Surg Res ; 15(1): 3, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900188

RESUMO

BACKGROUND: The relationship between spinal sagittal subtypes and lumbar disc degeneration is unclear. Thus, we aimed to investigate the relationship between lumbar intervertebral disc degeneration and age in asymptomatic healthy individuals with different sagittal alignments. METHODS: In this cross-sectional observational study, we examined 209 asymptomatic young and middle-aged volunteers (123 women and 86 men) who were divided into the following three groups according to age: groups A (20-30 years), B (31-40 years), and C (41-50 years). The volunteers underwent full-spine standing lateral radiography and magnetic resonance imaging (MRI, 3.0 T) of the lumbar spine. Based on panoramic radiography, two observers measured the spinopelvic parameters and classified the spine into Roussouly subtypes. The degree of disc degeneration was assessed based on T2-weighted images according to the Pfirrmann classification. RESULTS: There was a statistically significant difference in the degree of degeneration of type I spine between groups B and C at L4-L5 (P < 0.03) and L5-S1 (P < 0.01) and between groups A and C at L1-L2 (P < 0.04) and L4-L5 (P < 0.01). The degeneration degree of type II spine at all levels were significantly different between groups A and C. No statistically significant difference was found between groups A and B in all subtypes except for type II spine at L1-L2 (P < 0.04). A significant difference was found at four levels between groups B and C in type III spine (P < 0.05) and between groups A and C. For type IV spine, there was a significant difference in the degree of degeneration at L4-L5 (P < 0.02) between groups A and C. Moreover, almost all single parameters were not strongly correlated with the degree of disc degeneration. CONCLUSION: The different spinal subtypes have characteristics of lumbar disc degeneration at specific levels with age. We considered that spinal classification could be used as a predictor of lumbar disc degeneration. Our data may be helpful to increase awareness of the relationship between spinal subtypes and lumbar disc degeneration. LEVEL OF EVIDENCE: 3.


Assuntos
Doenças Assintomáticas/epidemiologia , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/epidemiologia , Vértebras Lombares/diagnóstico por imagem , Adulto , Fatores Etários , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética/tendências , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Int J Pharm ; 570: 118648, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31465833

RESUMO

Skin is the first protection of human body. It is always challenged by a range of external factors, resulting in the wounds of skin. Hydrogel, as a dressing with multiple advantages, causes increasing interests or the applications in wound treatment. However, the function and importance of micro-environment of wound region are frequently neglected. In this study, we successfully developed a chemokine loaded biomimetic hydrogel as a functional reservoir to stimulate the rapid in situ recruitment of BMSCs for fast wound repair and regeneration. The biomimetic hydrogel was fabricated by using the Polyvinyl alcohol (PVA) combined with chitosan (CS) as the hybrid materials. The fabricated hydrogel possesses many features such as the porous structure, high swelling rate and moisture retention property. More importantly, the incorporated chemokine could be released with a sustained manner from the hydrogel and recruited the bone marrow mesenchymal stem cells (BMSCs) significantly both in vitro & in vivo. Moreover, the hydrogel was demonstrated to be highly biocompatible to the skin tissue without any side effect or irritation observed. Topical delivery of chemokine by the biomimetic PVA/CS hybrid material based hydrogel is demonstrated as a promising carrier to accelerate wound repair and regeneration without inducing scar formation and any other negative complications. The PVA/CS/SDF-1 hydrogel was shown a novel therapeutic system for wound therapy.


Assuntos
Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/química , Quimiocinas/metabolismo , Regeneração/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Bandagens , Biomimética/métodos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Hidrogéis/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Álcool de Polivinil/química , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/metabolismo
11.
Biomed Res Int ; 2019: 1434538, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30993110

RESUMO

Osteoarthritis (OA) is a chronic degenerative joint disease, where chondrocyte apoptosis is responsible for cartilage degeneration. Bax is a well-known proapoptotic protein of the Bcl-2 family, involved in a large number of physiological and pathological processes. However, the regulation mechanisms of Bax underlying chondrocyte apoptosis in OA remain unknown. In the present study, we determined the role of Bax in human OA and chondrocyte apoptosis. The results showed that Bax was upregulated in chondrocytes from the articular cartilage of OA patients and in cultured chondrocyte-like ATDC5 cells treated by IL-1ß. Bax was identified to be the direct target of miR-29a by luciferase reporter assay and by western blotting. Inhibition of miR-29a by the mimics protested and overexpression by miR-29a inhibitors aggravated ATDC5 apoptosis induced by IL-1ß. These data reveal that miR-29a/Bax axis plays an important role in regulating chondrocyte apoptosis and suggest that targeting the proapoptotic protein Bax and increasing expression levels of miR-29a emerge as potential approach for protection against the development of OA.


Assuntos
Apoptose , Condrócitos/metabolismo , Regulação da Expressão Gênica , MicroRNAs/biossíntese , Osteoartrite/metabolismo , Proteína X Associada a bcl-2/biossíntese , Idoso , Idoso de 80 Anos ou mais , Condrócitos/patologia , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Osteoartrite/genética , Osteoartrite/patologia , Proteína X Associada a bcl-2/genética
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(2): 390-395, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-30998143

RESUMO

OBJECTIVE: To investigate the efficacy, prognosis and safety of decitabine combined with low-dose CAG regimen in the treatment of elderly patients with acute myeloid leukemia (AML). METHODS: The clinical data of 40 elderly patients with relapsed/refractory AML (69-85 years old) admitted to our hospital from January 2014 to August 2016 were analyzed retrospectively. 40 patients were divided into combination therapy group and CAG group according to different treatment methods. 20 patients of the combination therepy group were treated with decitabine combined with low-dose CAG (decitabine, 15 mg/m2, d 1; aclarithromycin, 10 mg/m2, d 3-6; Cytidine, 10 mg/m2, d 1-14; recombinant human granulocyte macrophage colony-stimulating factor (G-CSF) for injection, 200 µg/(m2·d), d 1-14). 20 patients of CAG group were treated by the standard CAG protocol (acralmycin 20 mg/m2, d 1-4; cytarabine for injection, 15 mg/m2, d 1-14; G-CSF 400 µg/(m2·d), d 1-14). One course of treatment lasted for 2 weeks, after 2 courses of continuous medication, the complete remission rate (CR), overall remission rate (ORR), overall survival (OS), 1-year survival rate, hemoglobin, white blood cells, platelets improvement, and incidence of adverse reactions were compared. RESULTS: In combination therapy group the CR was 55.00% (11/20), OR was 85.00% (17/20), but in the CAG group CR was 30.00% (6/20), and OR was 50.00% (10/20). Till to February 2018, out of 40 patients 17 survived, 20 died, and 3 failed to be followed-up. The median follow-up time was 12 (2 to 35) months; the median survival time in the comtination therapy group was 13 (2-35) months, and the 1-year OS rate was 70.00%, and the median survival time of the CAG group was 10 (2-31) months, and the 1-year OS rate was 50.00%, without staistical significance between the 2 groups (P>0.05). After treatment, the WBC and Plt counts in the combination therapy group were higher than those in the CAG group, but the Hb level was lower than that in the CAG group with statistically significant difference (P<0.05). In the combination therapy group, the incidence of lung infection, nausea and vomiting was higher than that of the CAG group (65.00% vs 25.00%, 50.00% vs 20.00%), with statistically significant difference (P<0.05). CONCLUSION: Decitabine combined with low-dose CAG regimen is effective for the treatment of relapsed/refractory AML in the elderly. Compared with the standard CAG regimen, the long-term efficacy of this regimen is not different significantly, but its adverse reactions are increase, thus the preventive treatment should be given in time.


Assuntos
Leucemia Mieloide Aguda , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina/administração & dosagem , Decitabina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
13.
Prog Mol Subcell Biol ; 58: 61-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911889

RESUMO

Lignocellulosic biomass has been widely studied as the renewable feedstock for the production of biofuels and biochemicals. Budding yeast Saccharomyces cerevisiae is commonly used as a cell factory for bioconversion of lignocellulosic biomass. However, economic bioproduction using fermentable sugars released from lignocellulosic feedstocks is still challenging. Due to impaired cell viability and fermentation performance by various inhibitors that are present in the cellulosic hydrolysates, robust yeast strains resistant to various stress environments are highly desired. Here, we summarize recent progress on yeast strain development for the production of biofuels and biochemical using lignocellulosic biomass. Genome-wide studies which have contributed to the elucidation of mechanisms of yeast stress tolerance are reviewed. Key gene targets recently identified based on multiomics analysis such as transcriptomic, proteomic, and metabolomics studies are summarized. Physiological genomic studies based on zinc sulfate supplementation are highlighted, and novel zinc-responsive genes involved in yeast stress tolerance are focused. The dependence of host genetic background of yeast stress tolerance and roles of histones and their modifications are emphasized. The development of robust yeast strains based on multiomics analysis benefits economic bioconversion of lignocellulosic biomass.


Assuntos
Biocombustíveis/provisão & distribuição , Etanol/metabolismo , Estudo de Associação Genômica Ampla , Lignina/metabolismo , Saccharomyces cerevisiae/classificação , Saccharomyces cerevisiae/metabolismo , Perfilação da Expressão Gênica , Metabolômica , Proteômica , Saccharomyces cerevisiae/genética
14.
Biomed Pharmacother ; 113: 108597, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30851547

RESUMO

Cigarette smoke (CS) exposure and Candida albicans (C. albicans) infection are epidemiological risk factors for oral diseases, such as oral leukoplakia (OLK). Smoking-induced inflammation and immune modulation are potentially important mechanisms in the development of diseases, although the biological mechanism of how CS exposure impacts host defenses has not been elucidated. The critical components of host defense, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and IL-1ß, are required for normal immune function in order to efficiently control infection. This paper studies the molecular mechanism of the immune-suppressive effect of CS on the oral mucosa of animal models. Rats were exposed to intraoral CS to simulate active human smoking and/or to C. albicans for 3 months or 6 months, and their ability to control the infection of C. albicans was examined. The CS and C. albicans co-exposed rats showed early stage lesions of OLK and were more susceptible to C. albicans than those in the C. albicans-exposed group. CS caused a reduced expression of the NLRP3 inflammasome and diminished the secretion of IL-1ß and IL-18 maturing by the NLRP3 inflammasome, which were stimulated by C. albicans. CS and immune suppression appear to be closely interwoven at multiple levels. This is the first animal model of active smoking through the mouth, and these data demonstrate that CS suppresses the protective immune response to C. albicans in rats through the NLRP3 inflammasome.


Assuntos
Candida albicans/patogenicidade , Candidíase Bucal/etiologia , Interações entre Hospedeiro e Microrganismos/imunologia , Inflamassomos/metabolismo , Mucosa Bucal/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fumar/efeitos adversos , Animais , Candidíase Bucal/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Imunidade Inata , Mucosa Bucal/microbiologia , Ratos Wistar , Saliva/imunologia , Fumar/imunologia
15.
FASEB J ; 33(4): 4836-4850, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30601695

RESUMO

Oxidative stress-induced vascular endothelial cell (VEC) injury is a major mechanism in the initiation and development of atherosclerosis. Lunasin, a soybean-derived 43-aa peptide, has been previously shown to possess potent antioxidant and anti-inflammatory activities other than its established anticancer activities. This study investigated the effects of lunasin on protecting VECs from oxidative damage and inhibiting atherosclerotic plaque progression in apolipoprotein E-deficient (ApoE-/-) mice and explored its underlying mechanism. Biochemical and histologic analyses were performed by using EA.hy926 human VECs and a high-fat diet (HFD) ApoE-/- mouse atherosclerosis model. Our data indicated that lunasin attenuated H2O2-induced, mitochondria-dependent endothelial apoptosis via down-regulating Bax and up-regulating Bcl-2, inhibiting the mitochondrial depolarization, and reducing the release of cytochrome c, as well as decreasing the activation of caspase-9 and caspase-3 in vitro and in vivo. Mechanic studies showed that lunasin significantly up-regulated heme oxygenase-1 via the PI3K/Akt/nuclear factor erythroid 2-related factor 2/antioxidant response element pathway, and reduced H2O2-induced ROS production in VECs, thereby attenuating oxidant-induced endothelial injury and inhibiting atherosclerotic plaque progression in ApoE-/- mice. In conclusion, our in vitro and in vivo data suggest that lunasin protects VECs from oxidative damage by enhancing heme oxygenase-1 expression via activation of the PI3K/Akt/nuclear factor erythroid 2-related factor 2/antioxidant response element pathway and inhibiting mitochondria-dependent apoptosis, thereby effectively attenuating atherosclerosis in HFD-fed ApoE-/- mice. Lunasin may act as a potential therapeutic agent for the prevention and treatment of atherosclerosis.-Gu, L., Ye, P., Li, H., Wang, Y., Xu, Y., Tian, Q., Lei, G., Zhao, C., Gao, Z., Zhao, W., Tan, S. Lunasin attenuates oxidant-induced endothelial injury and inhibits atherosclerotic plaque progression in ApoE-/- mice by up-regulating heme oxygenase-1 via PI3K/Akt/Nrf2/ARE pathway.


Assuntos
Apolipoproteínas E/metabolismo , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Plantas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apolipoproteínas E/genética , Apoptose/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos
16.
Toxicol Ind Health ; 35(2): 109-118, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30558485

RESUMO

Cigarette smoking is an established risk factor for some oral diseases. As an essential fluid in the oral cavity, saliva is crucial to maintain oral health. Relative to active smoking, there are very few studies assessing the effect of passive smoking on salivary cytokines levels. In the present study, we established the rat models by the means of the intraoral cigarette smoking or whole body cigarette smoke exposure to simulate human active or passive smoking, respectively. The effects of active or passive smoking on salivary cytokines levels were assessed by using ProcartaPlex multiplex immunoassays. The results of the current study indicated that both active and passive smoking diminished the body weights of rats and increased the levels of some blood counts. Intriguingly, active smoking enhanced the salivary levels of IL-6 and IL-12 p70 and passive smoking elevated the salivary IL-6 level. Moreover, active smoking appeared to have a more prominent activation effect on the salivary IL-6 level. It was noted that active or passive smoking had no significant effect on the salivary IFN-γ level. Active or passive smoking could have potential effects on the salivary levels of some pro-inflammatory cytokines.


Assuntos
Citocinas/análise , Saliva/química , Fumar/fisiopatologia , Poluição por Fumaça de Tabaco/análise , Animais , Peso Corporal , Feminino , Interleucina-6/análise , Masculino , Projetos Piloto , Ratos , Ratos Wistar
17.
MAbs ; 10(6): 864-875, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30081724

RESUMO

MBS301, a glyco-engineered bispecific anti-human epidermal growth factor receptor 2 (HER2) antibody with a typical IgG1 monoclonal antibody structure, was developed through dual-cell expression and in vitro assembling process. MBS301 consists of two half antibodies engineered from trastuzumab and pertuzumab, respectively. Integrity and purity profiles of MB301 indicated that the heterodimerization of the two half antibodies was successful. The high and similar melting temperatures (Tm1,72.0°C and Tm2, 84.8°C) of MBS301 compared with those of its parental monoclonal antibodies trastuzumab and pertuzumab (in-house made T-mab and P-mab, respectively) revealed its structural compactness. With computer-modeling experiments and Biacore binding and competition kinetics studies, the binding stoichiometry between MBS301 and HER2-ECD was determined to be 1:1 and the two arms of MBS301 were shown to bind to domains II and IV of HER2-ECD antigen simultaneously. MBS301 displayed synergistic bioactivities as the combination of T-mab and P-mab in vitro in multiple cancer cell lines and in vivo in xenograft mouse model studies, and showed more effective activity than T-mab or P-mab used individually. Moreover, fucose-knockout dramatically increased MBS301's binding affinity to low affinity FcγRIIIa allotype 158F (KD = 2.35 × 10-7M) to near the high affinity level of allotype V158 (KD = 1.17 × 10-7M). This resulted in far more effective ADCC activity of MBS301 than the combination of T-mab and P-mab in killing HER2-positive cancer cells. Hence, a novel fully afucosylated anti-HER2 bispecific antibody with improved antitumor activities was generated and shown to have the potential to be used for treating HER2-positive but trastuzumab-resistant solid tumors.


Assuntos
Anticorpos Biespecíficos/imunologia , Anticorpos Monoclonais/imunologia , Imunoglobulina G/imunologia , Receptor ErbB-2/imunologia , Animais , Anticorpos Biespecíficos/metabolismo , Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/metabolismo , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Linhagem Celular Tumoral , Feminino , Fucose/metabolismo , Glicosilação , Humanos , Imunoglobulina G/química , Imunoglobulina G/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Conformação Proteica , Receptor ErbB-2/metabolismo , Trastuzumab/química , Trastuzumab/imunologia , Trastuzumab/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Mol Sci ; 19(6)2018 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891775

RESUMO

Late blight caused by the oomycete fungus Phytophthora infestans (Pi) is the most serious obstacle to potato (Solanum tuberosum) production in the world. A super race isolate, CN152, which was identified from Sichuan Province, China, could overcome nearly all known late blight resistance genes and caused serious damage in China. The potato genotype SD20 was verified to be highly resistant to CN152; however, the molecular regulation network underlying late blight resistance pathway remains unclear in SD20. Here, we performed a time-course experiment to systematically profile the late blight resistance response genes using RNA-sequencing in SD20. We identified 3354 differentially expressed genes (DEGs), which mainly encoded transcription factors and protein kinases, and also included four NBS-LRR genes. The late blight responsive genes showed time-point-specific induction/repression. Multi-signaling pathways of salicylic acid, jasmonic acid, and ethylene signaling pathways involved in resistance and defense against Pi in SD20. Gene Ontology and KEGG analyses indicated that the DEGs were significantly enriched in metabolic process, protein serine/threonine kinase activity, and biosynthesis of secondary metabolites. Forty-three DEGs were involved in immune response, of which 19 were enriched in hypersensitive response reaction, which could play an important role in broad-spectrum resistance to Pi infection. Experimental verification confirmed the induced expression of the responsive genes in the late blight resistance signaling pathway, such as WRKY, ERF, MAPK, and NBS-LRR family genes. Our results provided valuable information for understanding late blight resistance mechanism of potato.


Assuntos
Resistência à Doença/genética , Perfilação da Expressão Gênica , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Solanum tuberosum/genética , Solanum tuberosum/microbiologia , Análise por Conglomerados , Regulação da Expressão Gênica de Plantas , Ontologia Genética , Genótipo , Anotação de Sequência Molecular , Doenças das Plantas/imunologia , Folhas de Planta/genética , Folhas de Planta/microbiologia , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Transdução de Sinais , Solanum tuberosum/imunologia , Transcriptoma/genética
19.
Biomed Pharmacother ; 101: 219-227, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29494959

RESUMO

OBJECTIVE: MicroRNAs (miRNAs) play an essential role in regulating malignant progression of tumour cells by inhibiting translation or stability of messenger RNA. However, the expression pattern and regulatory mechanism of miR-27-3p in osteosarcoma remains unclear. METHODS: We examined the expression of miR-27-3p in 5 osteosarcoma cell lines compared with that in 2 normal osteocyte cell lines. Osteosarcoma cells U-2OS and MG-63 were transduced to up-regulate or down-regulate the expression of miR-27-3p. The 3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide, or MTT, assay, colony formation assays, BrdUrd labelling, immunofluorescence, anchorage-independent growth ability assay and flow cytometry analysis were used to test the effect of miR-27-3p. Luciferase assays were added to verify the direct relationship between miR-27-3p and the predicted target gene inhibitor of growth family member 5 (ING5). RESULTS: The expression of miR-27-3p was significantly increased in examined osteosarcoma cell lines compared with that in normal osteocyte cell lines. Up-regulation of miR-27-3p significantly accelerated osteosarcoma cell growth via promoting G1-S transition. In addition, the opposite result was observed in miR-27-3p-down-regulated cells. Up-regulation of ING5 significantly attenuated the miR-27-3p-induced proliferation in osteosarcoma cells. CONCLUSIONS: These data suggested that miR-27-3p could promote the G1-S phase transition that leads to proliferation by down-regulating the expression of ING5 in osteosarcoma.


Assuntos
Neoplasias Ósseas/genética , MicroRNAs/genética , Osteossarcoma/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Neoplasias Ósseas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Citometria de Fluxo , Imunofluorescência , Fase G1/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Osteócitos/metabolismo , Osteossarcoma/patologia , Fase S/genética , Regulação para Cima
20.
Mol Med Rep ; 16(4): 4777-4783, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28849042

RESUMO

To the best of our knowledge, our previous study demonstrated the expression of triggering receptor expressed on myeloid cells 2 (TREM­2) in human bone marrow mesenchymal stem cells (MSCs) for the first time. However, the inflammation regulatory role of TREM­2 in MSCs remain elusive. The aim of the present study was to investigate the immune regulation and the underlying mechanism of TREM­2 in rat bone marrow MSCs. MSCs were divided into three groups: NullMSCs, TREM­2MSCs, and NormMSCs. TREM­2 was expressed in MSCs at the mRNA and protein level. Following stimulation by lipopolysaccharide (LPS), the gene transcription levels of TREM­2 and inflammatory cytokines were increased. The expression levels of inflammatory cytokines, including tumor necrosis factor­α (TNF­α) and interleukin­1ß (IL­1ß), in the TREM­2MSCs lentiviral vector group were significantly downregulated, and the expression of IL­10 was significantly upregulated compared with the controls. Western blot analysis revealed that TREM­2 downregulated the LPS­induced inflammatory response in MSCs, which was probably associated with regulating AKT serine/threonine kinase and p38 mitogen­activated protein kinase downstream signaling proteins. The results of the current study demonstrated that TREM­2 negatively regulates the LPS­mediated inflammatory response in MSCs suggesting that TREM­2 is a potential target of immune regulation in rat MSCs.


Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Lipopolissacarídeos/efeitos adversos , Células-Tronco Mesenquimais/metabolismo , Animais , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Expressão Gênica , Mediadores da Inflamação/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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